TY - JOUR. T1 - Compound heterozygosity for a hemizygous rare missense variant (rs141999351) and a large CNV deletion affecting the FSTL5 gene in a patient with schizophrenia. AU - Gardella, Rita. AU - Sacchetti, Emilio. AU - Legati, Andrea. AU - Magri, Chiara. AU - Traversa, Michele. AU - Gennarelli, Massimo. PY - 2016/10/29. Y1 - 2016/10/29. N2 - HighlightsWe identified a potential damaging variant in the FSTL5 gene of a schizophrenia patient.The patient was also a carrier of a CNV deleting almost the whole FSTL5 gene.Our findings are consistent with the double-hit hypothesis of schizophrenia.FSTL5 may be a candidate gene in schizophrenia.. AB - HighlightsWe identified a potential damaging variant in the FSTL5 gene of a schizophrenia patient.The patient was also a carrier of a CNV deleting almost the whole FSTL5 gene.Our findings are consistent with the double-hit hypothesis of schizophrenia.FSTL5 may be a candidate gene in schizophrenia.. UR - ...

Coarctation of the aorta (CoA) accounts for 4-8% of congenital heart defects (CHDs) and carries substantial morbidity despite treatment. We performed a genome-wide association study (GWAS) of CoA among 120 Icelandic cases and 355,166 controls and found association with a rare (frequency = 0.34%) missense mutation p.Arg721Trp in MYH6 (odds ratio (OR) = 44.2, P = 5.0x10-22), encoding an essential sarcomere protein. Approximately 20% of CoA cases in Iceland carry p.Arg721Trp. This is the first mutation associated with non-familial or sporadic CoA at a population level. P.Arg721Trp also associates with risk of bicuspid aortic valve (BAV) and other CHDs and has been reported to have a broad effect on cardiac electrical function and to associate strongly with sick sinus syndrome (SSS) and atrial fibrillation (AF). These findings suggest that p.Arg721Trp in MYH6 causes a cardiac syndrome with highly variable expressivity, and emphasize the major importance of sarcomere integrity for cardiac development ...

Notch1 has been regarded as a fundamental regulator in tissue differentiation and stem cell properties. Recently, Notch1 mutations have been reported intensively both in solid tumors and in hematopoietic malignancies. However, little is known about the biological effect and the clinical implication of these reported mutations. Previously, we discovered several missense mutations in the Notch1 receptor in a Chinese population with oral squamous cell carcinoma (OSCC). We selected a hotspot mutation in the Abruptex domain (C1133Y). The expression of Notch1 was determined by western blot and real-time qPCR in OSCC cell lines transfected with pcDNA3.1-Notch1WT, pcDNA3.1-Notch1C1133Y, or pcDNA3.1 empty vector. CCK-8 assays were used to assess cell proliferation. Flow cytometry and western blot were used to confirm the alteration of cell cycle after transfection. Transwell assays and the detection of Epithelial-to-mesenchymal transition (EMT) markers were used to determine the invasive ability. The effects

A Novel Heterozygous Missense Variant (c.667G,T;p.Gly223Cys) in USH1C That Interferes With Cadherin-Related 23 and Harmonin Interaction Causes Autosomal Dominant Nonsyndromic Hearing Loss. ...

We describe a novel homozygous missense glucokinase mutation (R397L) resulting in insulin-treated neonatal diabetes in an infant from a consanguineous Asian family. Both parents were heterozygous for R397L and had mild hyperglycemia. Glucokinase mutations should be considered in infants of all ethnic groups with neonatal diabetes and consanguinity.

Author: Mohamed, Salah A. et al.; Genre: Journal Article; Published in Print: 2006-07-14; Keywords: NOTCH1; Bicuspid aortic valve; Valve calcification; Missense mutations; Title: Novel missense mutations (p.T596M and p.P1797H) in NOTCH1 in patients with bicuspid aortic valve

Molecular anomalies in MED13L, leading to haploinsufficiency, have been reported in patients with moderate to severe intellectual disability (ID) and distinct facial features, with or without congenital heart defects. Phenotype of the patients was referred to MED13L haploinsufficiency syndrome. Missense variants in MED13L were already previously described to cause the MED13L-related syndrome, but only in a limited number of patients. Here we report 36 patients with MED13L molecular anomaly, recruited through an international collaboration between centers of expertise for developmental anomalies. All patients presented with intellectual disability and severe language impairment. Hypotonia, ataxia, and recognizable facial gestalt were frequent findings, but not congenital heart defects. We identified seven de novo missense variations, in addition to protein-truncating variants and intragenic deletions. Missense variants clustered in two mutation hot-spots, i.e., exons 15-17 and 25-31. We found that

Each persons genome sequence has thousands of missense variants. Practical interpretation of their functional significance must rely on computational inferences in the absence of exhaustive experimental measurements. Here we analyzed the efficacy of these inferences in 33 de novo missense mutations …

In contrast to the typical Pierson syndrome phenotype, which has been associated primarily with null mutations in LAMB2,1,4 missense mutations, such as R246Q and C321R, cause mild variants of Pierson syndrome, in which congenital nephrotic syndrome is the predominant manifestation and extrarenal features are less pronounced.18 LAMB2 missense mutation is one of the most common disease-causing mutations in early onset nephrotic syndrome.39 Previously, we investigated the mechanisms whereby the R246Q mutation causes congenital nephrotic syndrome19; here, we determined how the C321R mutation causes proteinuria.. Our results suggest that the mechanisms responsible for nephrotic syndrome in patients harboring the C321R-LAMB2 mutation involve both severely impaired laminin secretion and concomitant podocyte ER stress-associated injury. Our hypothesis is supported by both in vivo and in vitro data. In vivo, we generated three lines of transgenic mice, in which C321R-LAMB2 mRNA was expressed in podocytes ...

Mutations in SLC6A1, encoding γ-aminobutyric acid (GABA) transporter 1 (GAT-1), have been recently associated with a spectrum of epilepsy syndromes, intellectual disability and autism in clinic. However, the pathophysiology of the gene mutations is far from clear. Here we report a novel SLC6A1 missense mutation in a patient with epilepsy and autism spectrum disorder and characterized the molecular defects of the mutant GAT-1, from transporter protein trafficking to GABA uptake function in heterologous cells and neurons. The heterozygous missense mutation (c1081C to A (P361T)) in SLC6A1 was identified by exome sequencing. We have thoroughly characterized the molecular pathophysiology underlying the clinical phenotypes. We performed EEG recordings and autism diagnostic interview. The patient had neurodevelopmental delay, absence epilepsy, generalized epilepsy, and 2.5-3 Hz generalized spike and slow waves on EEG recordings. The impact of the mutation on GAT-1 function and trafficking was evaluated by 3H

article{ad4911a9-fa37-43c8-88dd-95a7ab3e310d, abstract = {,p,ABHD12 mutations have been linked to neurodegenerative PHARC (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and early-onset cataract), a rare, progressive, autosomal, recessive disease. Although ABHD12 is suspected to play a role in the lysophosphatidylserine and/or endocannabinoid pathways, its precise functional role(s) leading to PHARC disease had not previously been characterized. Cell and zebrafish models were designed to demonstrate the causal link between an identified new missense mutation p.T253R, characterized in ABHD12 from a young patient, the previously characterized p.T202I and p.R352* mutations, and the associated PHARC. Measuring ABHD12 monoacylglycerol lipase activity in transfected HEK293 cells demonstrated inhibition with mutated isoforms. Both the expression pattern of zebrafish abhd12 and the phenotype of specific antisense morpholino oligonucleotide gene knockdown morphants were consistent with human ...

ATM is the gene mutated in the autosomal recessive disorder Ataxiatelangiectasia (A-T). Female relatives of A-T patients carrying a heterozygous A-T mutation have an increased breast cancer risk but it was not known if ATM mutations that were not pathogenic for A-T were associated with breast cancer risk. In a large combined analysis, Fletcher and colleagues genotyped 5 polymorphic missense ATM SNPs in 26,101 breast cancer cases from 23 different studies. The authors report that the 5 missense ATM SNPs were associated with a small increased risk of breast cancer. This study illustrates how testing the combined effects of rare missense variants in known breast cancer genes can help clarify their overall contribution to breast cancer susceptibility. ...

In this study, systematic inhibitor response to ErbB missense mutations in gastric cancer (GC) is investigated by combining computational analysis and experimental assay. The response profile is created for 6 ATP-competitive, reversible inhibitors against 9, 17, 5 and 17 GC-associated missense mutations of ErbB1, ErbB2, ErbB3 and ErbB4 kinase domains, respectively. From the profile a number of p...

Homozygous mutations in TREM2 are known to cause rare, autosomal recessive forms of dementia with an early onset and presenting with[6] or without[8] bone cysts and fractures. A rare missense mutation (rs75932628-T) in the gene encoding TREM2, (predicted to result in an R47H substitution), confers a significant risk of Alzheimers disease. Given the reported antiinflammatory role of TREM2 in the brain, it is suspected of interfering with the brains ability to prevent the buildup of plaque.[9][10] TREM2 mutations increase the risk of neurodegenerative conditions such as Alzheimers disease, amyotrophic lateral sclerosis, and Parkinsons disease. TREM2 interacts with DAP12 in microglia to trigger phagocytosis of amyloid beta peptide and apoptotic neurons without inflammation. Mutations in TREM2 impair the normal proteolytic maturation of the protein which in turn interferes with phagocytosis and may therefore contribute to the pathogenesis of Alzheimers disease.[11] Soluble TREM2 has been ...

ACTB encodes β-actin, an abundant cytoskeletal housekeeping protein. In humans, postulated gain-of-function missense mutations cause Baraitser-Winter syndrome (BRWS), characterized by intellectual disability, cortical malformations, coloboma, sensorineural deafness, and typical facial features. To date, the consequences of loss-of-function ACTB mutations have not been proven conclusively. We describe heterozygous ACTB deletions and nonsense and frameshift mutations in 33 individuals with developmental delay, apparent intellectual disability, increased frequency of internal organ malformations (including those of the heart and the renal tract), growth retardation, and a recognizable facial gestalt (interrupted wavy eyebrows, dense eyelashes, wide nose, wide mouth, and a prominent chin) that is distinct from characteristics of individuals with BRWS. Strikingly, this spectrum overlaps with that of several chromatin-remodeling developmental disorders. In wild-type mouse embryos, β-actin expression ...

Although improvements in genetic analysis have greatly enhanced our understanding of the mechanisms behind pancreatitis, it continues to afflict many families for whom the hereditary factors remain unknown. Recent evaluation of a patient with a strong family history of pancreatitis prompted us to reexamine a large kindred originally reported over 50 years ago with an autosomal-dominant inheritance pattern of chronic pancreatitis, diabetes, and pancreatic adenocarcinoma. Whole-exome sequencing analysis identified a rare missense mutation in the gene encoding pancreas-specific protease elastase 3B (CELA3B) that cosegregates with disease. Studies of the mutant protein in vitro, in cell lines, and in CRISPR-Cas9-engineered mice indicate that this mutation causes translational upregulation of CELA3B, which, upon secretion and activation by trypsin, leads to uncontrolled proteolysis and recurrent pancreatitis. Although lesions in several other pancreatic proteases have been previously linked to ...

Although improvements in genetic analysis have greatly enhanced our understanding of the mechanisms behind pancreatitis, it continues to afflict many families for whom the hereditary factors remain unknown. Recent evaluation of a patient with a strong family history of pancreatitis prompted us to reexamine a large kindred originally reported over 50 years ago with an autosomal-dominant inheritance pattern of chronic pancreatitis, diabetes, and pancreatic adenocarcinoma. Whole-exome sequencing analysis identified a rare missense mutation in the gene encoding pancreas-specific protease elastase 3B (CELA3B) that cosegregates with disease. Studies of the mutant protein in vitro, in cell lines, and in CRISPR-Cas9-engineered mice indicate that this mutation causes translational upregulation of CELA3B, which, upon secretion and activation by trypsin, leads to uncontrolled proteolysis and recurrent pancreatitis. Although lesions in several other pancreatic proteases have been previously linked to ...

Although improvements in genetic analysis have greatly enhanced our understanding of the mechanisms behind pancreatitis, it continues to afflict many families for whom the hereditary factors remain unknown. Recent evaluation of a patient with a strong family history of pancreatitis prompted us to reexamine a large kindred originally reported over 50 years ago with an autosomal-dominant inheritance pattern of chronic pancreatitis, diabetes, and pancreatic adenocarcinoma. Whole-exome sequencing analysis identified a rare missense mutation in the gene encoding pancreas-specific protease elastase 3B (CELA3B) that cosegregates with disease. Studies of the mutant protein in vitro, in cell lines, and in CRISPR-Cas9-engineered mice indicate that this mutation causes translational upregulation of CELA3B, which, upon secretion and activation by trypsin, leads to uncontrolled proteolysis and recurrent pancreatitis. Although lesions in several other pancreatic proteases have been previously linked to ...

Although improvements in genetic analysis have greatly enhanced our understanding of the mechanisms behind pancreatitis, it continues to afflict many families for whom the hereditary factors remain unknown. Recent evaluation of a patient with a strong family history of pancreatitis prompted us to reexamine a large kindred originally reported over 50 years ago with an autosomal-dominant inheritance pattern of chronic pancreatitis, diabetes, and pancreatic adenocarcinoma. Whole-exome sequencing analysis identified a rare missense mutation in the gene encoding pancreas-specific protease elastase 3B (CELA3B) that cosegregates with disease. Studies of the mutant protein in vitro, in cell lines, and in CRISPR-Cas9-engineered mice indicate that this mutation causes translational upregulation of CELA3B, which, upon secretion and activation by trypsin, leads to uncontrolled proteolysis and recurrent pancreatitis. Although lesions in several other pancreatic proteases have been previously linked to ...

Congenital heart defects (CHDs) are the most common birth defect worldwide and are a leading cause of neonatal mortality. Nonsyndromic atrioventricular septal defects (AVSDs) are an important subtype of CHDs for which the genetic architecture is poorly understood. We performed exome sequencing in 13 parent-offspring trios and 112 unrelated individuals with nonsyndromic AVSDs and identified five rare missense variants (two of which arose de novo) in the highly conserved gene NR2F2, a very significant enrichment (p = 7.7 × 10(-7)) compared to 5,194 control subjects. We identified three additional CHD-affected families with other variants in NR2F2 including a de novo balanced chromosomal translocation, a de novo substitution disrupting a splice donor site, and a 3 bp duplication that cosegregated in a multiplex family. NR2F2 encodes a pleiotropic developmental transcription factor, and decreased dosage of NR2F2 in mice has been shown to result in abnormal development of atrioventricular septa. Via

BACKGROUND: Genetic testing for breast cancer susceptibility is widely used, but for many genes, evidence of an association with breast cancer is weak, underlying risk estimates are imprecise, and reliable subtype-specific risk estimates are lacking. METHODS: We used a panel of 34 putative susceptibility genes to perform sequencing on samples from 60,466 women with breast cancer and 53,461 controls. In separate analyses for protein-truncating variants and rare missense variants in these genes, we estimated odds ratios for breast cancer overall and tumor subtypes. We evaluated missense-variant associations according to domain and classification of pathogenicity. RESULTS: Protein-truncating variants in 5 genes (ATM, BRCA1, BRCA2, CHEK2, and PALB2) were associated with a risk of breast cancer overall with a P value of less than 0.0001. Protein-truncating variants in 4 other genes (BARD1, RAD51C, RAD51D, and TP53) were associated with a risk of breast cancer overall with a P value of less than 0.05 ...

The consequences of base substitution mutations in protein coding regions of a gene depend on the substitution and its location. They may be silent, not resulting in a new amino acid in the protein sequence, eg. GCA or GCG codons in mRNA both mean arginine [this is often true in the third position of a codon, especially with transitions because of wobble base pairing]. A base substitution could also result in an amino acid substitution; this is referred to as a missense mutation. For example, CTC in the DNA sense strand [GAG in mRNA] will specify a glutamate residue in the protein; this is altered to CAC in the DNA or GUG in the mRNA, resulting in a valine residue in the beta-globin protein chain causing sickle-cell anemia. Missense mutations may have very serious consquences, as in the case of sickle-cell anemia, mild consequences as in the case of hemoglobin C (a different amino acid substitution in position 6 of beta-globin) or no phenotype as in the case of two known amino acid ...

EXTL3 regulates the biosynthesis of heparan sulfate (HS), important for both skeletal development and hematopoiesis, through the formation of HS proteoglycans (HSPGs). By whole-exome sequencing, we identified homozygous missense mutations c.1382C|T, c.1537C|T, c.1970A|G, and c.2008T|G in …

We developed a sequence context based model of de novo mutations to create per-gene probabilities of mutation. We noticed a high correlation (0.94) between the probability of a synonymous mutation in a gene and the number of rare synonymous variants identified in that same gene first using the NHLBI. s Exome Sequencing Project data (evs.gs.washington.edu), then with 25,000 exomes analyzed simultaneously (see abstract by MacArthur et al). We predicted the number of variants that we would expect to see in the dataset and, in order to quantify deviations, created a Z score of the chi-squared difference between observation and expectation for both synonymous and missense variation. While the distribution of these Z scores for the synonymous variants was normal, there is a marked shift in the missense distribution towards having fewer variants than predicted ...

The R1195H variant of uncertain significance in the FBN2 gene has not been published as pathogenic or been reported as benign to our knowledge. R1195H is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R1195H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved in mammals, however, H1195 is the wild-type residue in at least one species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Finally, although located within a calcium-binding EGF-like domain of the FBN2 gene, the R1195H variant does not affect a Cysteine residue. Cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with ...

This sequence change replaces lysine with glutamic acid at codon 132 of the TP53 protein (p.Lys132Glu). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is present in population databases (rs747342068, ExAC 0.002%). This variant has been reported in a single family affected with Li-Fraumeni syndrome. Currently there is insufficient evidence to conclude whether this variant segregates with disease or not (PMID: 9157982). Experimental studies have reported that cells carrying this missense change have reduced TP53 expression levels and transactivation activities, which results in the loss of normal TP53 functions in cell cycle and apoptosis control (PMID: 9157982, 21343334). A separate study testing TP53 transactivation activity of 8 different promoters also classifies this missense change as non-functional (PMID: 12826609). In summary, this is a rare missense change that is reported in an affected family and seen ...

With increasing use of multi-gene panel tests, one of the genes in which mutations are frequently detected among breast cancer patients and others is the CHEK2 gene. This gene has been shown to have a 2-3 fold excess risk for breast cancer. There are many CHEK2 mutations that have been identified that generally fall into two broad categories: those that prematurely shorten the protein that is made from the gene (called truncating mutations) and those that change a single base pair within the gene that impairs it from working normally (called missense mutations). Most completed studies have focused on a specific truncating mutation called 1100delC, as it is a relatively common change particularly among European populations.. A few studies have tried to assess if breast cancers associated with CHEK2 mutations may have specific characteristics, although results have not been consistent. For example, a study from 2014 which included 3 CHEK2 truncating mutations (including the 1100delC ...

The horizontal axis represents time, and the vertical axis represents a percentage of the population. When a mutation enters the population, it occurs in only one individual and is plotted as a point somewhere on the x axis. If the mutation is passed on, for example to four new offspring, then it will be in a higher percentage of the population at the next time step. Most mutations will soon drop out of the population. Either the individual where the mutation originates will not survive, or if it does survive and mate, by chance it may not pass the mutation to its children. Even then the children may not pass the mutation any further. Mutations that eventually die out show up as inverted ``V shapes in the figure: they are introduced, they are passed on to some proportion of the population in the next few generations, and eventually the percentage drops to 0 as the mutation disappears. Some small percentage of new mutations are passed on successfully. If by chance the mutation continues to ...

Six novel missense mutations (H29D, L35P, G84R, C96S, S101C, and Y103C) were identified in seven families. Three of these mutations involve cysteine residues within the insulin A chain and are therefore predicted to affect the normal folding of the proinsulin molecule. S101C was identified in two families: in ISPAD180 the finding that both children are heterozygous for the mutation but neither parent is a carrier suggests that the mutation has arisen de novo in one parent who must be a germline mosaic (Fig. 2). In the second family, the mutation was not present in the unaffected father, but DNA was not available from the mother.. The novel C96S mutation occurs at the site of a previously reported mutation (C96Y) identified in a patient with PND (10) and in the Akita mouse model (11). The same amino acid substitution (Cys,Ser) is present at the adjacent residue (C95S) in the Munich mouse model (23). Studies of these mice indicate that mutant proinsulin is trapped and accumulated in the ER, ...

sage -t --long devel/sage/sage/combinat/cluster_algebra_quiver/mutation_type.py ********************************************************************** File devel/sage/sage/combinat/cluster_algebra_quiver/mutation_type.py, line 1259, in sage.combinat.cluster_algebra_quiver.mutation_type._mutation_type_test Failed example: _mutation_type_test(2) # long time Expected: True (A, 2) True (A, (1, 1), 1) True (B, 2) True (BC, 1, 1) True (G, 2) Got: True (A, (1, 1), 1) True (A, 2) True (B, 2) True (BC, 1, 1) True (G, 2) ********************************************************************** File devel/sage/sage/combinat/cluster_algebra_quiver/mutation_type.py, line 1266, in sage.combinat.cluster_algebra_quiver.mutation_type._mutation_type_test Failed example: _mutation_type_test(3) # long time Expected: True (A, 3) True (A, (2, 1), 1) True (B, 3) True (BB, 2, 1) True (BC, 2, 1) True (C, 3) True (CC, 2, 1) True (G, 2, -1) True (G, 2, 1) Got: True (A, (2, 1), 1) ...

Description of disease Gain-of-function mutation. Treatment Gain-of-function mutation. Symptoms and causes Gain-of-function mutation Prophylaxis Gain-of-function mutation

Family history showed that the patients father had developed muscle weakness and atrophy in his upper extremities at 50 years of age, and died of pneumonia at 72 years of age. However, her mother was healthy and died of chronic renal failure at 80 years of age. Her elder sister was, at the time of writing, 73 years of age and healthy. Her elder brother displayed muscle weakness and wasting in his upper limbs and was diagnosed with ALS at 46 years of age. He also had mild cognitive impairment 10 years after onset. He died from respiratory failure 15 years after symptom onset. Her younger sister developed weakness in her right hand at 50 years of age. She was diagnosed with ALS at 58 years of age. There are no affected members in the third generation of this family; however, they are all younger than 35 years of age.. A novel missense mutation (C to A codon 41 in exon 2) that resulted in an amino acid substitution of glycine to aspartate (G41D) was identified in participants II-2, II-3, II-4, ...

Charité - Universitätsmedizin Berlin, Experimental and Clinical Research Center (ECRC) bietet Stelle als Cell biological analysis of BAG3 missense mutants causing cardiomyopathy

Description: Goniodysgenesis (GG) is caused by abnormal development of the anterior chamber of the eye. Due to abnormal development of intraocular fluid egress channels inside the eye the iridocorneal angle (ICA), through which the excessive chamber fluid is filtered and drained. Within dog, population goniodysgenesis is considered as a congenital disease, which can often cause glaucoma or blindness. For first was GG detected in Border Collies in the late 90s in Australia, after that it spread to Europe and USA.. Goniodysgenesis has two forms: severe and mild. The severe form of this disease is caused by the mutation in the gene encoding for olfactomedin-like 3 (OLFML3). This encoded protein facilitates protein-protein interactions, cell adhesion, and intracellular interactions and has a general supporting function. It seems that the mild form of the disease is not associated with this mutation and can be caused by other genetic predispositions. GG is caused by a missense mutation c.590G,A ...

On Fri, Jul 22, 2011 at 2:08 AM, Dave Raggett ,[email protected], wrote: , On 22/07/11 02:26, Adam Klein wrote: ,, ,, This is only complex because youre coalescing the mutations, right? ,, In Rafaels original proposal, each mutation would result in a single ,, immutable mutation record, so the semantics would be to deliver (by ,, appending to a queue associated with each observer) a mutation record ,, to any currently-registered observers. ,, ,, Or is there some other concern with beginning notifications partway ,, through a task? , , I would suggest avoiding coalescing mutations altogether! , , But if you are going to, *dont* coalesce mutations when the resulting DOM , tree is dependent on the order in which those mutations took place. This is , critical to distributed editing applications. The DOM should have no such behavior. The only exception to this rule that I know of is ,script, elements. They execute their contained script the first time they are inserted into a Document, but dont undo ...

For position 29 only BLOSSUM62 says that this mutation is not likely. The 9 other sources show that this mutation wont have a damaging influence on the function or structure of the protein. This is perspicuous since the conservation of this position is not very high. The amino acid on position 125 is quite good conserved with 96%. SNAP and SIFT says that this mutation will have an influence on the protein whereas Polyphen2 says that this mutation is ether not (HumVar) or hardly damaging (HumDiv). Since this position is quite good conserved it is more likely that this mutation will have an influence on the function or structure of the protein. back to Maple_syrup_urine_disease main page go back to Task 5 Mapping SNPs ...

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Investigation Dna Proteins And Mutations Answer Key. Point mutations that occur in dna sequences encoding proteins are either silent, missense or nonsense. Copying errors when dna replicates or is transcribed into rna can cause changes in the sequence of bases which makes up the genetic code. Mutations mutations the genes encoded in your dna result […]

These are internal identifiers that are unique to a mutation on a particular transcript and are displayed in the URL of the mutation pages. Therefore, several of these internal ids could be associated with a single genomic COSV id where the mutation has been mapped to all overlapping genes and transcripts. Similarly, since every COSM id is mapped to one COSV id (where genomic coordinates are known), each COSM id can also be associated with several alternative (internal) identifiers. These ids are expected to change between assemblies (GRCh37 and GRCh38) and between the releases ...

Get an answer for Which of the two types of mutations, nonsense or missense, would be more harmful to an organism? and find homework help for other Biology questions at eNotes

Supplementary MaterialsS1 Fig: Verification of ER-resident E3 ubiquitin ligases for SLO-1 degradation. a known ER stress inducer. Data are means SEM; NS, not significant, One-way ANOVA; Tukeys post hoc test). (level pub = 10 m).(TIF) pgen.1008829.s002.tif (593K) GUID:?DBE63996-C89E-4F82-881B-7FFAF2BF049C S3 Fig: A mutation reverses the reduced SLO-1 function in the absence of ERG-28. A mutation raises aldicarb resistance in animals. Aldicarb-induced paralysis was analyzed using Kaplan-Meier success evaluation.(TIF) pgen.1008829.s003.tif (330K) GUID:?27E62CCF-E0A9-4960-B343-65FD7739843D S4 Fig: An mutation will not impede the trafficking of overexpressed SLO-1. (A) Consultant pictures and quantification of SLO-1 on the dorsal cable of mutant pets. No aggregated puncta had been observed (range club = 10 m).(TIF) pgen.1008829.s004.tif (1.0M) GUID:?AB4CE45E-2E16-4600-9923-5ABFB0F9CBFE S5 Fig: The deletion mutation recovers higher degrees of SLO-1 on the dorsal cord compared to the missense mutation. ...

In this rar are the contents of the hdd mutation sits on. It contains the current (non-functioning) source code as well as multiple source backups I had made throughout its development. The current source code is capable of importing tags from other projects, but when I last touched it I was in the middle of writing code to explode the sound_diagnostics tag at decompile time, and rebuilding it at compile time from the sound tags. So in its current state it will not work for anything, if it even compiles without errors. I would check the last source backup to see if it can import tags, since it could prove useful to some people. I would also like to say that this project is the result of many years of work, coding styles, and ideas. It is a mess and does not reflect my current coding ability. My only request is that if you choose to do anything to Mutation and release it, please release it under another name with credit to the mutation source code. I have a vision in my head of what Mutation ...

A) in a published family with nonsyndromic MR, MRX13. This change occurs in a highly conserved amino acid, with proline (P) being substituted by threonine (T) (p.P544T). Functional analysis shows that this amino-acid substitution compromises both tri- and didemethylase activity of the JARID1C protein. We conclude that the two novel changes impair JARID1C protein function and are disease-causing mutations in these families ...

TY - JOUR. T1 - Novel TGM1 missense mutation p.Arg727Gln in a case of self-healing collodion baby. AU - Tanahashi, Kana. AU - Sugiura, Kazumitsu. AU - Asagoe, Kenji. AU - Aoyama, Yumi. AU - Iwatsuki, Keiji. AU - Akiyama, Masashi. PY - 2014/1/1. Y1 - 2014/1/1. UR - http://www.scopus.com/inward/record.url?scp=84906054613&partnerID=8YFLogxK. UR - http://www.scopus.com/inward/citedby.url?scp=84906054613&partnerID=8YFLogxK. U2 - 10.2340/00015555-1765. DO - 10.2340/00015555-1765. M3 - Comment/debate. C2 - 24419105. AN - SCOPUS:84906054613. VL - 94. SP - 589. EP - 590. JO - Acta Dermato-Venereologica. JF - Acta Dermato-Venereologica. SN - 0001-5555. IS - 5. ER - ...

The β-cell-enriched MAFA transcription factor plays a central role in regulating glucose-stimulated insulin secretion while also demonstrating oncogenic transformation potential in vitro. No disease-causing MAFA variants have been previously described. We investigated a large pedigree with autosomal dominant inheritance of diabetes mellitus or insulinomatosis, an adult-onset condition of recurrent hyperinsulinemic hypoglycemia caused by multiple insulin-secreting neuroendocrine tumors of the pancreas. Using exome sequencing, we identified a missense MAFA mutation (p.Ser64Phe, c.191C,T) segregating with both phenotypes of insulinomatosis and diabetes. This mutation was also found in a second unrelated family with the same clinical phenotype, while no germline or somatic MAFA mutations were identified in nine patients with sporadic insulinomatosis. In the two families, insulinomatosis presented more frequently in females (eight females/two males) and diabetes more often in males (12 males/four ...

TY - JOUR. T1 - A novel missense mutation in the second extra cellular domain of GJB2, p.Ser183Phe, causes a syndrome of focal palmoplantar keratoderma with deafness. AU - de Zwart-Storm, E. A.. AU - van Geel, M.. AU - van Neer, P. A.F.A.. AU - Steijlen, P. M.. AU - Martin, Patricia E.M.. AU - van Steensel, M. A.M.. N1 - Originally published in: American Journal of Pathology (2008), 173 (4), pp.1113-11179.. PY - 2008/10/1. Y1 - 2008/10/1. N2 - Gap junctions, which consist of connexins, are intercellular channels that mediate rapid intercellular communication. In the skin, connexins are involved in the regulation of epidermal growth and differentiation. GJB2 encodes connexin26, which is an important skin-expressed gap junction protein. Mutations in GJB2 cause a wide variety of unique disorders, but despite extensive research, their mechanisms of action are poorly understood. The identification of novel diseases caused by mutations in GJB2 may help to illuminate the genotype-phenotype correlation ...

title: Hereditary Protein C Deficiency with Recurrent Thrombosis Identification of a Missense Mutation (C6218T), doi: 10.3346/jkms.1998.13.2.186, category: Article

A recent study described a recessive ATPase activating germ-line mutation in smooth-muscle myosin (smmhc/myh11) underlying the zebrafish meltdown (mlt) phenotype. The mlt zebrafish develops intestinal abnormalities reminiscent of human Peutz-Jeghers syndrome (PJS) and juvenile polyposis (JP). To examine the role of MYH11 in human intestinal neoplasia, we searched for MYH11 mutations in patients with colorectal cancer (CRC), PJS and JP. We found somatic protein-elongating frameshift mutations in 55% of CRCs displaying microsatellite instability and in the germ-line of one individual with PJS. Additionally, two somatic missense mutations were found in one microsatellite stable CRC. These two missense mutations, R501L and K1044N, and the frameshift mutations were functionally evaluated. All mutations resulted in unregulated molecules displaying constitutive motor activity, similar to the mutant myosin underlying mlt. Thus, MYH11 mutations appear to contribute also to human intestinal neoplasia. Unregulated

We previously described an endogamous Pakistani kindred in whom we identified a novel homozygous missense mutation in the PRKCD gene encoding for protein kinase C δ (PKCδ) as a cause of monogenic systemic lupus erythematosus (SLE). PKCδ has a role in the negative regulation of B cells. Given the nature of the disease, a logical targeted therapeutic approach in these patients is B cell depletion. Indeed, the 3 siblings all had a marked clinical response and resolution of symptoms with rituximab, although 2 of the siblings had severe reactions to rituximab thus precluding further treatment with this. We therefore describe the first successful use of ofatumumab for this rare form of monogenic SLE. All three affected siblings presented with SLE before the age of 3-years with lethargy, intermittent fever, thrombocytopenia, cutaneous involvement, alopecia, and hepatosplenomegaly. Tubulointerstitial nephritis was also present in 1 of the siblings. Homozygosity mapping followed by whole exome sequencing

TY - JOUR. T1 - A homozygous missense variant in the alkaline phosphatase gene ALPL is associated with a severe form of canine hypophosphatasia. AU - Kyöstilä, Kaisa. AU - Syrjä, Pernilla. AU - Lappalainen, Anu K.. AU - Arumilli, Meharji. AU - Hundi, Sruthi. AU - Karkamo, Veera. AU - Viitmaa, Ranno. AU - Hytönen, Marjo K.. AU - Lohi, Hannes. PY - 2019/1/30. Y1 - 2019/1/30. KW - PYRIDOXINE-RESPONSIVE SEIZURES. KW - INFANTILE HYPOPHOSPHATASIA. KW - MATRIX VESICLES. KW - PERINATAL HYPOPHOSPHATASIA. KW - MUTATION. KW - BONE. KW - VITAMIN-B6. KW - NOSOLOGY. KW - GENOTYPE. KW - PYRIDOXAL-5-PHOSPHATE. KW - 413 Veterinary science. KW - 1184 Genetics, developmental biology, physiology. KW - 3111 Biomedicine. U2 - 10.1038/s41598-018-37801-2. DO - 10.1038/s41598-018-37801-2. M3 - Article. VL - 9. JO - Scientific Reports. JF - Scientific Reports. SN - 2045-2322. M1 - 973. ER - ...

Limb girdle muscular dystrophy 2B (LGMD2B) is without treatment and caused by mutations in the dysferlin gene (DYSF). One third are missense mutations leading to dysferlin aggregation and amyloid formation in addition to defects in sarcolemmal repair and progressive muscle wasting. Dysferlin-null mouse models do not allow to study the consequences of missense mutations. We generated a new mouse model (MMex38) carrying a missense mutation in exon 38 in analogy to a clinically relevant human DYSF variant (DYSF p.Leu1341Pro). The targeted mutation induces all characteristics of missense mutant dysferlinopathy including a progressive dystrophic pattern, amyloid formation and defects in membrane repair. We chose U7 snRNAs-based splice switching to demonstrate a possible exon skipping strategy in this new animal model. We show that Dysf exons 37 and 38 can successfully be skipped in vivo. Overall, the MMex38 mouse model provides an ideal tool for preclinical development of treatment strategies for ...

Autosomal dominant hypocalcaemia type 1 (ADH1) is a rare familial disorder characterised by low serum calcium and low or inappropriately normal serum PTH. It is caused by activating CASR mutations, which produces a left-shift in the set point for extracellular calcium. We describe an Australian family with a novel heterozygous missense mutation in CASR causing ADH1. Mild neuromuscular symptoms (paraesthesia, carpopedal spasm) were present in most affected individuals and required treatment with calcium and calcitriol. Basal ganglia calcification was present in three out of four affected family members. This case highlights the importance of correctly identifying genetic causes of hypocalcaemia to allow for proper management and screening of family members. ...

Recently, missense mutations in titin-associated proteins have been linked to the pathogenesis of dilated cardiomyopathy (DCM). The objective of this study was to search for novel disease-associated mutations in the two human titin-binding proteins myopalladin and its amino-terminal-interacting partner cardiac ankyrin-repeat protein (CARP). In a cohort of 255 cases with familial and sporadic DCM, we analyzed the coding regions and all corresponding intron flanks located in the MYPN and CARP-encoding ANKRD1 gene. Two heterozygous missense mutations were detected in the MYPN gene (p.R955W and p.P961L), but neither of these mutations was found in 300 healthy controls. Both mutations were located in the alpha-actinin-binding region of myopalladin. Endomyocardial biopsies from the p.R955W carrier showed normal subcellular localization of myopalladin and alpha-actinin in cardiac myocytes, while their regular sarcomeric staining pattern was significantly disrupted in the p.P961L carrier, indicating ...

UniProt Consortium, Apweiler R, Martin MJ, ODonovan C, Magrane M, Alam-Faruque Y, Antunes R, Barrell D, Bely B, Bingley M, Binns D, Bower L, Browne P, Chan WM, Dimmer E, Eberhardt R, Fazzini F, Fedotov A, Foulger R, Garavelli J, Castro LG, Huntley R, Jacobsen J, Kleen M, Laiho K, Legge D, Lin Q, Liu W, Luo J, Orchard S, Patient S, Pichler K, Poggioli D, Pontikos N, Pruess M, Rosanoff S, Sawford T, Sehra H, Turner E, Corbett M, Donnelly M, van Rensburg P, Xenarios I, Bougueleret L, Auchincloss A, Argoud-Puy G, Axelsen K, Bairoch A, Baratin D, Blatter MC, Boeckmann B, Bolleman J, Bollondi L, Boutet E, Quintaje SB, Breuza L, Bridge A, deCastro E, Coudert E, Cusin I, Doche M, Dornevil D, Duvaud S, Estreicher A, Famiglietti L, Feuermann M, Gehant S, Ferro S, Gasteiger E, Gateau A, Gerritsen V, Gos A, Gruaz-Gumowski N, Hinz U, Hulo C, Hulo N, James J, Jimenez S, Jungo F, Kappler T, Keller G, Lara V, Lemercier P, Lieberherr D, Martin X, Masson P, Moinat M, Morgat A, Paesano S, Pedruzzi I, Pilbout S, ...

Background: Cataract is a major cause of severe visual impairment in childhood. The purpose of this study was to determine the genetic cause of syndromic congenital cataract in an Australian mother and son.Method: Fifty-one genes associated with congenital cataract were sequenced in the proband using a custom Ampliseq library on the Ion Torrent Personal Genome Machine (PGM). Reads were aligned against the human genome (hg19) and variants were annotated. Variants were prioritised for validation by Sanger sequencing if they were novel, rare or previously reported to be associated with paediatric cataract and were predicted to be protein changing. Variants were assessed for segregation with the phenotype in the affected mother.Result: A novel likely pathogenic variant was identified in the transactivation domain of the MAF gene (c.176C , G, p.(Pro59Arg)) in the proband and his affected mother., but was absent in 326 unrelated controls and absent from public variant databases.Conclusion: The MAF ...

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WES of 91 men in 19 HPC families, followed by replication (n = 130 candidate variants) in an independent set of 270 HPC families and further testing of candidate variants with replication support (n = 2) in a population-based case-control study, provides compelling evidence that rare germline variants in butyrophilin-like 2 (BTNL2) are associated with genetic susceptibility to prostate cancer. These rare missense variants, rs41441651 (exon 5; D336N) and rs28362675 (exon 6; G454C), occur in the same haplotype block on chromosome 6p21.32 and were observed to be in strong linkage disequilibrium among controls in the case-control dataset (r2 = 0.99). This is the first WES study focused on aggressive or early-onset prostate cancer phenotypes and the first to implicate rare germline BTNL2 variants as predisposing to familial and sporadic prostate cancer.. There is some prior suggestive evidence for a role of BTNL2 in prostate cancer. A recent exome sequencing study of prostate tumor tissue from 50 ...

Mutations in the |i|COL4A3|/i| gene are frequently reported to be associated with various types of hereditary nephropathy. |i|COL4A3|/i| encodes the |i|α|/i|3 chain of type IV collagen, which is the main structural protein in the basement membrane. Mutations in this gene are always related to kidney performance, and deafness and ocular lesion have also been reported. In this study, using next-generation sequencing, we investigated the DNA of a family visiting a clinic for hearing loss. A new missense mutation was found in |i|COL4A3|/i| of 5 patients, c.3227C>T (p.P1076L). Based on these results, we predict that the mutation is pathogenic and leads to abnormal collagen IV. Here, we report for the first time on this autosomal dominant syndrome, characterized by hearing loss and eye abnormalities, but without renal damage, in all carriers. Since the oldest patient in the trial was less than 50 years old, however, we recommend that renal examination be reviewed regularly. Our results reveal

TY - JOUR. T1 - Generation of the first autosomal dominant osteopetrosis type II (ADO2) disease models. AU - Alam, Imranul. AU - Gray, Amie K.. AU - Chu, Kang. AU - Ichikawa, Shoji. AU - Mohammad, Khalid S.. AU - Capannolo, Marta. AU - Capulli, Mattia. AU - Maurizi, Antonio. AU - Muraca, Maurizio. AU - Teti, Anna. AU - Econs, Michael J.. AU - Del Fattore, Andrea. PY - 2014/2. Y1 - 2014/2. N2 - Autosomal dominant osteopetrosis type II (ADO2) is a heritable osteosclerotic disorder dependent on osteoclast impairment. In most patients it results from heterozygous missense mutations in the chloride channel 7 (CLCN7) gene, encoding for a 2Cl-/1H+ antiporter. By a knock-in strategy inserting a missense mutation in the Clcn7 gene, our two research groups independently generated mouse models of ADO2 on different genetic backgrounds carrying the homolog of the most frequent heterozygous mutation (p.G213R) in the Clcn7 gene found in humans. Our results demonstrate that the heterozygous model holds true ...

Retinoic acid (RA), the active metabolite of vitamin A, broadly regulates gene expression. The RA signaling pathway plays an essential role in embryonic development, including the development of the body axis, eye, brain, and heart (Ghyselinck & Duester, 2019). One of the key enzymes in the biosynthesis of RA is aldehyde dehydrogenase 1 family member A3 (ALDH1A3). ALDH1A3 converts retinaldehyde to retinoic acid and it is expressed early in forebrain development (McCaffery & Drager, 1994). Several mutations in ALDH1A3 have been implicated in patients with autosomal recessive microphthalmia and other neurological disorders (Fares-Taie et al., 2013; Roos et al., 2014). However, current animal models of ALDH1A3 have large truncations of the protein. Direct evidence of the effects of missense variants on ALDH1A3 protein activity has not yet been obtained.. In this study, we aimed to determine the functional consequence of ALDH1A3(C174Y) missense variants implicated in patients (Roos et al., 2014). ...

THE number of compensatory mutations that will affect a specific deleterious mutation is a fundamental evolutionary quantity of which little is known. A mutation is compensatory if it has a beneficial effect on fitness that is conditional on the presence of a deleterious mutation at a different site in the genome (Kimura 1985). Hence, a compensatory effect is the outcome of a strong epistatic interaction between two mutations. Each compensatory mutation represents an alternate genetic solution to adaptation; thus, fitness recovery from the accumulation of deleterious mutations becomes less likely to occur by back mutation when compensatory mutations are increasingly common (Whitlock and Otto 1999). Indeed, one must invoke a compensatory mutation to explain the rapid, stepwise recovery of fitness observed in mutationally degraded experimental populations (Burch and Chao 1999; Moore et al. 2000; Estes and Lynch 2003). Compensatory mutations are also implicated in the persistence of alleles that ...

The GluD2 protein, encoded by GRID2, is a member of the ionotropic glutamate receptor family that mediates excitatory synaptic transmission [17]. Studies on mice have revealed that Grid2 is expressed primarily in the Purkinje cells and it is essential for the formation and organization of synapses [23, 24]. Furthermore, mice with homozygous disruption of Grid2 show ataxia and mild cerebellar hypoplasia [25]. In humans, a few studies have recently reported on GRID2 gene variants in cerebellar syndrome with variable clinical expression. Characteristic features include slowly progressive SCA, ocular symptoms including upgaze and nystagmus, hypotonia, developmental delay with cognitive decline, and reduced volume of cerebellar vermis. The symptoms have been associated with both biallelic or monoallelic mutations indicating alternate patterns of inheritance [3-7].. Our combined data show that a novel and homozygous missense variant in the GRID2 gene is associated with the clinical features in our ...

It is very nice for you to answer my question so specific.. I think my work should be related with the first one. After reading your answer, I still have two questions about it.. 1. According to your answer, the mutations seen in both tumor and matched normal samples are usally germline, so I wonder, do the germline mutations, which can be detected from normal tissues of this patient, are eliminated from the somatic mutations, listed in that publication? (I guess if we check and search mutations in the tumor tissues of one patient, it is impossible to determine whether one mutation is belong to the somatic mutations or germline mutations, inherited from his parents. Unless we make the same analysis to the normal tissues of this patient and find the germline mutations of s/he, can we make sure which is somatic mutation and which is germline mutation.). 2. I just make sure Im clear about what you say. Most of the mutations for samples like TCGA-02-0047-11A-01D-1490-08 are belong to germline ...

Higashide T, Wada T, Sakurai M, Yokoyama H, Sugiyama K. Macular abnormalities and optic disk anomaly associated with a new PAX2 missense mutation. Am J Ophthalmol. 2005 Jan;139(1):203-5.. ...

Genetic mutations have two major types: large mutation (deletion, insertion, duplication, and inversion) and point mutation (nonsense, missense, and frame shift). Some mutations can induce DNA transcription and translation errors eventually causing protein dysfunction that leads to disease [1, 2]. Currently, many whole genome scale association studies between disease and variation are being published [3]. However, medical researchers have had to go through mutations in patient DNA to detect mutations that may be the cause of a disease [4, 5].. There are many human disease gene databases that contain disease-causing mutation information as locus-specific databases (LSDBs). Also, large databases, such as Online Mendelian Inheritance in Man (OMIM) [6] and the Human Gene Mutation Database (HGMD) [7], collect and describe comprehensively all disease-related genes. In contrast, LSDBs usually describe variations in a small number of genes. The LSDBs aim to provide particular genetic mutation ...

TY - JOUR. T1 - Mutation screening of the DYT6/THAP1 gene in Italy. AU - Albanese, Alberto. AU - Bentivoglio, Anna Rita. AU - Ialongo, Tamara. AU - Piano, Carla. AU - Petracca, Martina. AU - Bonetti, M. AU - Barzaghi, C. AU - Brancati, F. AU - Ferraris, A. AU - Bellacchio, E. AU - Giovanetti, A. AU - Zorzi, Giovanna. AU - Nardocci, Nardo. AU - Dallapiccola, B. AU - Garavaglia, B. AU - Valente, Em. PY - 2009. Y1 - 2009. N2 - Mutations in the THAP1 gene on chromosome 8p21-p22 (DYT6 locus) have been recently reported as causative of autosomal dominant primary torsion dystonia (PTD) in four Amish-Mennonite families and in 12 additional probands of different ancestry. We sequenced the THAP1 gene in 158 patients with DYT1-negative PTD who had onset of symptoms below 30 years and/or positive family history. One sporadic Greek male patient, aged 57 years, was found to carry a novel heterozygous missense variant in THAP1 exon 3 (p.Cys170Arg), of likely pathogenic significance. This subject first ...

Mutations are generally regarded as bad. Ive covered several on this blog, from the curious genetics of werewolves to homeotic mutations that turn arms into legs to the sad tales of neurologic disease and hereditary blindness.. But some mutations are good. Perhaps the best is the CCR5 mutation that keeps HIV out of our cells, a genetic glitch that drugs and gene therapy are trying to imitate. Most mutations, it seems, are neither evil nor beneficial, but neutral. After all, Henny lived in good health for 115 years, yet her blood cells still accrued 450 mutations.. DNA Science blog always tries to find a different perspective to genetics news, and for the case of Henny, it is the fact that mutations need not signal doom. Dr. Holstege had the idea to look at Hennys genome because of the role of somatic mutations in causing cancer. But another view is that many mutations do nothing at all.. Neutral mutations will impact the application of DNA sequencing in health care decision-making. The Nature ...

A mutation is any change occurring in the message that a gene carries. Mutations mainly arise as copy errors when DNA is replicated at mitosis and meiosis. Darwinian evolution requires a constant supply of variation: much of it is supplied by mutation, and a mutation-selection balance can maintain a genetic polymorphism. The first major geneticist to study mutation was H.J. Muller, who demonstrated it can be induced by X-rays. He also recognized that the rate of mutation in nature is extremely low, and that they are almost always deleterious to the fitness of the organism. The accumulation of deleterious mutations places a mutational load on the population. Mutations can occur at single base level or at chromosomal level. The effects of mutation can occasionally be very dramatic: some of these fruitflies have suffered mutations which alter the number of wings that develop... Is mutation directed?. ...

Define escape mutation. escape mutation synonyms, escape mutation pronunciation, escape mutation translation, English dictionary definition of escape mutation. n. 1. The act or process of being altered or changed. 2. An alteration or change, as in nature, form, or quality. 3. Genetics a. A change in the nucleotide...

The following figure shows the location of the disease-causing mutations in hKv8.2 in CDSRE patients examined in this study. Three of these, W450G, G459D, and G461R, are located in the pore region of the hKv8.2 α-subunit. The missense mutations G459D and G461R affect the first and second glycine, respectively, of the Gly-Tyr-Gly motif, the characteristic potassium channel signature sequence. To understand the functional consequences of these mutations, the corresponding mutations (W467G, G476D, and G478R) were introduced into mKv8.2, and their effect on subunit localization in COS7L cells was examined. Like mKv8.2, the expression of either mKv8.2-W467G-EGFP, mKv8.2-G476D-EGFP, or mKv8.2-G478R-EGFP resulted in an intracellular localization [1753]. Voltage-gated K+ channels selectively transfer potassium ions through the plasma membrane in response to depolarization. The ion-conducting core of voltage-gated K+ channels is composed of four Kv-alpha subunits, which also possess the voltage sensor. ...

Our results support the concept that variants in CTLA4 provide the basis for a novel Mendelian form of early-onset CD associated with systemic autoimmunity. Incomplete penetrance of autoimmunity further indicates the presence of other genetic and/or environmental modifiers.A novel missense variant was identified in CTLA4 encoding CTLA-4, a coinhibitory protein expressed by T cells and required for regulation of T cell activation. The residue affected by the mutation, CTLA-4 Tyr60, is evolutionarily highly conserved, and the identified Y60C variant is predicted to affect protein folding and structural stability and demonstrated to cause impaired CTLA-4 dimerisation and CD80 binding. Intestinal inflammation and autoimmunity in carriers of CTLA-4 Y60C exhibit incomplete penetrance with a spectrum of clinical presentations ranging from asymptomatic carrier status to fatal autoimmunity and intestinal inflammation. In a clinically affected CTLA-4 Y60C carrier, T cell proliferation was increased in ...

Germline mutations of transcription factors (e.g. PAX5, CEBPA, GATA2, RUNX1) have been associated with an inherited susceptibility to acute leukemia. Here we report 2 unrelated kindreds harboring germline mutations in ETV6, the gene encoding the transcription factor ETS variants 6. These kindreds were primarily characterized by thrombocytopenia and acute lymphoblastic leukemia (ALL). The first kindred, identified at MSKCC and HMC, includes 9 individuals with thrombocytopenia, and 3 individuals with pre-B ALL. Sequencing a subset of common and somatically altered leukemia genes in this family identified a rare heterozygous non-synonymous missense variation (T,C) in 6 family members with thrombocytopenia and 2 with ALL. Notably, this variant did not segregate in 9 individuals in the kindred without these phenotypes. The amino acid alteration is predicted to lead to an L349P substitution within the DNA binding domain of ETV6 (L349P, NPP_001978). In silico analyses using SIFT and Polyphen assigned ...

Mutation assays can then be grouped together into PCR arrays based off common themes to enable users to profile a focused set of mutations. The mutations on an array are selected based on a commonality, such as being from the same gene, signaling pathway, or cancer type. For example, users could profile the most common 84 mutations in breast cancer or the 44 most common mutations in APC. The Custom qBiomarker Somatic Mutation PCR Arrays allow users to select the mutations that they wish to profile. Together, the qBiomarker Somatic Mutation products facilitate sensitive detection and profiling of mutations in cancer cells or tumor samples ...

Casals T, Pacheco P, Barreto C, Gimenez J, Ramos MD, Pereira S, Pinheiro JA, Cobos N, Curvelo A, Vazquez C, Rocha H, Seculi JL, Perez E, Dapena J, Carrilho E, Duarte A, Palacio AM, Nunes V, Lavinha J, Estivill X Missense mutation R1066C in the second transmembrane domain of CFTR causes a severe cystic fibrosis phenotype: study of 19 heterozygous and 2 homozygous patients. 1997;10(5):387-92 ...

In this study ARMS has been found to be both more sensitive and robust at detecting somatic mutations in clinical material than DNA sequencing. There were no examples where ARMS did not detect an assay-specific mutation that was detected by DNA sequencing. There were 42 mutations detected by ARMS that were not detected by DNA sequencing either due to low quantity or quality DNA causing assay fails or low mutant DNA compared to normal DNA in the sample that was beyond the detection limit of sequencing. They were not believed to be false positive results as they were known mutations, the results were reproducible and adequate controls were analysed in parallel. There were 12 mutations detected by sequencing that were not detected by ARMS because the ARMS assays used were not designed to detect these mutations, either because the mutations were rare (melanoma study) or ARMS assays had not yet been developed to detect these mutations. However, using the larger panel of ARMS assays now available the ...

Figure. Xena Browser link-out to MuPIT 3D mutation view. On the left of the figure is Xena mutation column view of ERBB2 somatic mutations from the TCGA breast cancer cohort (https://xenabrowser.net/heatmap/?bookmark=6098aca9a00041d6271f18f2b471a241). User clicking on the MuPIT link-out menu (similar to how xena links out to Tumor Map), it will send all the mutations genomic positions as well as their recurrence p values to the MuPIT display. On the right side of the figure, MuPIT displays mutations in various size of bright green spheres. Large spheres for recurrent mutations. Size of the mutation spheres are determined by recurrence p values. The MuPIT display shows these ERBB2 somatic mutations cluster around the ERBB2 active site (ATP binding site in blue and proton acceptor site in teal).. ...

LITTLE excuse is needed for still being interested in mutation. We are here thanks to the germline mutations experienced by our ancestors, and, at least in the developed nations of the world, more of us die from somatic mutations than from any other single cause. For the evolutionary biologist, the process of mutation presents no problems. For anyone attempting an overview of cancer research, however, the process has become increasingly obscure. It was this obscurity that prompted my laboratory in the 1980s to look again at the interplay between mutation and selection.. Germline mutation: To some extent, the particular mutational changes that generated the evolutionary tree can be deduced from comparisons of the differences in sequence that distinguish the different branches of the tree. It is not easy, however, to investigate what were the causes of those changes. Perhaps for that reason, it is customary to think of mutation as being driven by chance events attributable to the natural ...

On average, Peruvian individuals are among the shortest in the world1. Here we show that Native American ancestry is associated with reduced height in an ethnically diverse group of Peruvian individuals, and identify a population-specific, missense variant in the FBN1 gene (E1297G) that is significantly associated with lower height. Each copy of the minor allele (frequency of 4.7%) reduces height by 2.2 cm (4.4 cm in homozygous individuals). To our knowledge, this is the largest effect size known for a common height-associated variant. FBN1 encodes the extracellular matrix protein fibrillin 1, which is a major structural component of microfibrils. We observed less densely packed fibrillin-1-rich microfibrils with irregular edges in the skin of individuals who were homozygous for G1297 compared with individuals who were homozygous for E1297. Moreover, we show that the E1297G locus is under positive selection in non-African populations, and that the E1297 variant shows subtle evidence of positive

Most truncation or deletion mutations underlying HI are thought to lead to severe loss of ABCA12 protein function affecting important nucleotide-binding fold domains and/or transmembrane domains. Thus far, in HI patients, at least one mutation on each allele must be a truncation or deletion mutation within a conserved region to cause serious loss of ABCA12. Complete loss of ABCA12 function due to homozygous or compound heterozygous truncation mutations always results in the HI patient phenotype. ...

Mutations are often the victims of bad press unfairly stereotyped as unimportant or as a cause of genetic disease. While many mutations do indeed have small or negative effects, another sort of mutation gets less airtime. Mutations to control genes can have major (and sometimes positive) effects. Some regions of DNA control other genes, determining when and where other genes are turned on. Mutations in these parts of the genome can substantially change the way the organism is built. The difference between a mutation to a control gene and a mutation to a less powerful gene is a bit like the difference between whispering an instruction to the trumpet player in an orchestra versus whispering it to the orchestras conductor. The impact of changing the conductors behavior is much bigger and more coordinated than changing the behavior of an individual orchestra member. Similarly, a mutation in a gene conductor can cause a cascade of effects in the behavior of genes under its control. ...

In their new paper, published in PNAS, the researchers show that the Tmem161b protein plays an important role in the regulation of the cardiac rhythm in at least two species: the zebrafish and the mouse. The researchers observed a disturbed cardiac rhythm in a group of zebrafish embryos and the cause was traced back to a mutation in Tmem161b. Likewise, mice that carried a mutation in this gene displayed abnormalities in heart function. Homozygous mutations - that is, mutations that occur on both copies of the gene - are incompatible with life; animals with this double mutation in Tmem161b die prematurely. This also appears to be the case in humans. Animals with a heterozygous mutation - a mutation on one copy of the gene - mature, but then appear more susceptible to developing cardiac arrythmias. We do not know yet whether this is also the case in humans. Further research is necessary to elucidate this, says Lotte Koopman, researcher on the project ...

The present study illustrates several striking features of the genetic diversity present in domestic animals. Firstly, the R2 allele exemplifies the evolution of alleles by two or more consecutive mutations. Other examples include the Dominant white allele in pigs which involves a 450 kb duplication encompassing the entire KIT gene combined with a splice mutation in one of the duplicated copies [31] and black spotting in pigs which is determined by the combined effects of two mutations in MC1R, a missense mutation associated with black colour and a somatically unstable two base-pair insertion [32]. Secondly, it represents a new example of how structural rearrangements have contributed to rapid phenotypic evolution observed in domestic animals [33], [34]. The majority of the structural changes reported to be associated with phenotypic effects, like the effects of R1 and R2 on comb morphology, constitute cis-acting regulatory mutations. The altered configurations of regulatory elements on the ...

Many mutations in cancer are of unknown functional significance. Standard methods use statistically significant recurrence of mutations in tumor samples as an indicator of functional impact. We extend such analyses into the long tail of rare mutations by considering recurrence of mutations in clusters of spatially close residues in protein structures. Analyzing 10,000 tumor exomes, we identify more than 3000 rarely mutated residues in proteins as potentially functional and experimentally validate several in RAC1 and MAP2K1. These potential driver mutations (web resources: 3dhotspots.org and cBioPortal.org) can extend the scope of genomically informed clinical trials and of personalized choice of therapy.

Mutation matrices have been frequently used to describe measures of physicochemical similarities among amino acids. Dayhoff et al. initially introduced the use of the mutation matrix, which was constructed from the phylogenetic analysis of 71 proteins with at least 85% pairwise sequence identity [1]. They observed point mutations in the matrices resulting from both the mutation of the gene itself, and the subsequent acceptance of the mutation, possibly as a predominant form. Not all possible replacements for an amino acid are acceptable, and the group of acceptable mutations vary from one protein family to another [1]. The Dayhoff matrix still ranks among the widely-used scoring schemes for generating multiple alignments, although there have been several modifications, such as the use of a larger number of more divergent protein sequences, as well as the generation of separate log-odds matrices for soluble and non-soluble proteins [2].. It remains difficult, however, to evaluate the effects of ...

Mutations . Section 12-4 This section describes and compares gene mutations and chromosomal mutations. Mutations. What are mutations? Mutations are changes in the DNA sequence that affect genetic information. Mutations. Is the following sentence true or false? Slideshow 1277847 by Patman

In the six families without detectable TP53germline mutation (fig 2), we then analysed theTP63 gene. To screen for inactivatingTP63 mutations, we performed a functional assay in yeast. Transformation of the pCI51 plasmid18containing the wild type coding region corresponding to the isoform γ of TP63 into the yIG397-RGC yeast reporter strain resulted in white colonies. Transformation of two mutant pCI51 plasmids (with the mutation Leu264Ser or Cys269Ser generated by PCR induced mutagenesis), used as controls, resulted only in red colonies. In four index cases, for whom mRNA was available, the TP63 cDNA was PCR amplified from lymphocytes between codons 18 and 434, cloned by homologous recombination into the gapped expression vector pCI51 linearised between codons 30 and 420, and transformed into yIG397-RGC; the percentage of red colonies (table 1) suggested the absence of heterozygous inactivating mutations. We also sequenced in the six families without detectable TP53 mutation exons 2 to 15 of ...

A recent study published in Nature has found that the age at which a father has children will determine how many mutations his offspring inherit. Pioneering geneticist J. B. S. Haldane in the 1930s, had worked years before the structure of DNA was determined, but according to Nature, he was correct about why fathers pass on more mutations than mothers. Sperm is continually being generated by dividing precursor cells, which acquire new mutations with each division. By contrast, women are born with their lifelong complement of egg cells, according to the article. The study found that fathers passed on nearly four times as many new mutations as mothers: on average, 55 versus 14.. Stefánssons team also found that the older a man gets, the more new mutations are passed on. A 36-year-old will pass on twice as many mutations to his child as a man of 20, and a 70-year-old eight times as many, his team estimated.. Since the average age of childbearing is rising, the study suggests that more ...

A gene mutation is a permanent alteration in the DNA sequence that makes up a gene, making the sequence differ from what is found in most people. Mutations can affect anywhere from a single DNA building block (base pair) to a large segment of a chromosome that includes multiple genes. There are two types of gene mutations. Hereditary mutations are inherited from a parent and are present throughout a persons life in virtually every cell in the body. Acquired mutations, sometimes called somatic mutations, occur at some time during a persons life and are present only in certain cells. These changes can be caused by environmental factors or can occur if a mistake is made as DNA copies itself during cell division. ...

The basic principle behind the data analysis is that we compare the Ct value of a mutation assay in a test sample with the Ct value of the same assay in a wildtype sample. When there is a significant difference (a preset value of 4 Cts) between the Ct values, the test sample is concluded to contain the mutation. The Ct values used for comparison can either be raw Ct (in average Ct method) or normalized Ct (in delta delta Ct case). When the Ct difference falls between 3 and 4, we give a borderline mutation call, which means that the mutation may be present at low percentage. When the Ct difference is smaller than 3, we give a negative mutation call (i.e. the mutation percentage is beyond the detection limit of the array). The wildtype sample can be either a genuine wildtype sample that is tested in the same experiment, or it could be a virtual wildtype sample that is computed from all test samples. For detailed description of the data analysis principle, refer to (link to white paper ...

The CD19 antigen, expressed on most B-cell acute lymphoblastic leukemias (B-ALL), can be targeted with chimeric antigen receptor-armed T cells (CART-19), but relapses with epitope loss occur in 10% to 20% of pediatric responders. We detected hemizygous deletions spanning the CD19 locus and de novo frameshift and missense mutations in exon 2 of CD19 in some relapse samples. However, we also discovered alternatively spliced CD19 mRNA species, including one lacking exon 2. Pull-down/siRNA experiments identified SRSF3 as a splicing factor involved in exon 2 retention, and its levels were lower in relapsed B-ALL. Using genome editing, we demonstrated that exon 2 skipping bypasses exon 2 mutations in B-ALL cells and allows expression of the N-terminally truncated CD19 variant, which fails to trigger killing by CART-19 but partly rescues defects associated with CD19 loss. Thus, this mechanism of resistance is based on a combination of deleterious mutations and ensuing selection for alternatively ...