Yin and yang 1 (YY1) is a well-known zinc-finger transcription factor with crucial roles in normal development and malignancy. YY1 acts both as a repressor and as an activator of gene expression. We have identified 23 individuals with de novo mutations or deletions of YY1 and phenotypic features that define a syndrome of cognitive impairment, behavioral alterations, intrauterine growth restriction, feeding problems, and various congenital malformations. Our combined clinical and molecular data define YY1 syndrome as a haploinsufficiency syndrome. Through immunoprecipitation of YY1-bound chromatin from affected individuals cells with antibodies recognizing both ends of the protein, we show that YY1 deletions and missense mutations lead to a global loss of YY1 binding with a preferential retention at high-occupancy sites. Finally, we uncover a widespread loss of H3K27 acetylation in particular on the YY1-bound enhancers, underscoring a crucial role for YY1 in enhancer regulation. Collectively, ...
J Clin Invest. 2011 Apr;121(4):1266-82. doi: 10.1172/JCI43452. Epub 2011 Mar 23. Research Support, N.I.H., Extramural; Research Support, Non-U.S. Govt
The plant life cycle includes diploid sporophytic and haploid gametophytic generations. Female gametophytes (embryo sacs) in higher plants are embedded in specialized sporophytic structures (ovules). Here, we report that two closely related mitogen-activated protein kinases in Arabidopsis thaliana, MPK3 and MPK6, share a novel function in ovule development: in the MPK6 mutant background, MPK3 is haplo-insufficient, giving female sterility when heterozygous. By contrast, in the MPK3 mutant background, MPK6 does not show haplo-insufficiency. Using wounding treatment, we discovered gene dosage-dependent activation of MPK3 and MPK6. In addition, MPK6 activation is enhanced when MPK3 is null, which may help explain why mpk3-/- mpk6+/- plants are fertile. Genetic analysis revealed that the female sterility of mpk3+/- mpk6-/- plants is a sporophytic effect. In mpk3+/- mpk6-/- mutant plants, megasporogenesis and megagametogenesis are normal and the female gametophyte identity is correctly established. ...
Haploinsufficiency of Meis1 is a potential model system for simulating RLS in mice. Here, we show that this Meis1 deficit causes a sex- and context-dependent RLS-related phenotype at middle age, impaired sensorimotor gating ability that was refractory to the D2/3R agonist pramipexole as well as increased social memory. These behavioral abnormalities occurred without differences in thermal sensitivity, plasma iron concentrations or dopaminergic neuron number in the SNpc/VTA. Thus, although Meis1 haploinsufficiency causes the RLS-related phenotype of motor restlessness in mice, the detailed nature of these effects is complex. Furthermore, it is characteristically distinct from other genetic RLS models (e.g. Btbd9 knock-out), highlighting the heterogeneous nature of the effects of these different risk genotypes in this disease.. Motor restlessness in these Meis1-haploinsufficient mice was detected previously in young adult male and female mice (Spieler et al., 2014). RLS is, however, more prevalent ...
p120-Catenin (p120) functions as a tumor suppressor in intestinal cancer, but the mechanism is unclear. Here, using conditional p120 knockout in Apc-sensitized mouse models of intestinal cancer, we have identified p120 as an "obligatory" haploinsufficient tumor suppressor. Whereas monoallelic loss of p120 was associated with a significant increase in tumor multiplicity, loss of both alleles was never observed in tumors from these mice. Moreover, forced ablation of the second allele did not further enhance tumorigenesis, but instead induced synthetic lethality in combination with Apc loss of heterozygosity. In tumor-derived organoid cultures, elimination of both p120 alleles resulted in caspase-3-dependent apoptosis that was blocked by inhibition of Rho kinase (ROCK). With ROCK inhibition, however, p120-ablated organoids exhibited a branching phenotype and a substantial increase in cell proliferation. Access to data from Sleeping Beauty mutagenesis screens afforded an opportunity to directly ...
p120-Catenin (p120) functions as a tumor suppressor in intestinal cancer, but the mechanism is unclear. Here, using conditional p120 knockout in Apc-sensitized mouse models of intestinal cancer, we have identified p120 as an "obligatory" haploinsufficient tumor suppressor. Whereas monoallelic loss of p120 was associated with a significant increase in tumor multiplicity, loss of both alleles was never observed in tumors from these mice. Moreover, forced ablation of the second allele did not further enhance tumorigenesis, but instead induced synthetic lethality in combination with Apc loss of heterozygosity. In tumor-derived organoid cultures, elimination of both p120 alleles resulted in caspase-3-dependent apoptosis that was blocked by inhibition of Rho kinase (ROCK). With ROCK inhibition, however, p120-ablated organoids exhibited a branching phenotype and a substantial increase in cell proliferation. Access to data from Sleeping Beauty mutagenesis screens afforded an opportunity to directly ...
p120-Catenin (p120) functions as a tumor suppressor in intestinal cancer, but the mechanism is unclear. Here, using conditional p120 knockout in Apc-sensitized mouse models of intestinal cancer, we have identified p120 as an "obligatory" haploinsufficient tumor suppressor. Whereas monoallelic loss of p120 was associated with a significant increase in tumor multiplicity, loss of both alleles was never observed in tumors from these mice. Moreover, forced ablation of the second allele did not further enhance tumorigenesis, but instead induced synthetic lethality in combination with Apc loss of heterozygosity. In tumor-derived organoid cultures, elimination of both p120 alleles resulted in caspase-3-dependent apoptosis that was blocked by inhibition of Rho kinase (ROCK). With ROCK inhibition, however, p120-ablated organoids exhibited a branching phenotype and a substantial increase in cell proliferation. Access to data from Sleeping Beauty mutagenesis screens afforded an opportunity to directly ...
Apoptosis is a well-described cell death pathway but the relationship between autophagy and cell death is controversial (34). The autophagy gene beclin 1 is a haploinsufficient tumor suppressor and increased expression of Beclin 1 in MCF-7 cells promotes autophagy and inhibits the formation of human breast tumors in mouse models (35). Autophagic cell death is sometimes described as programmed cell death II, and has been suggested as a new target for cancer therapy (36). However, it has been clearly documented that autophagy maintains cellular homeostatsis and can have both antitumor and tumor-promoting properties (37). Recently, autophagy has been shown to promote ras-driven tumor growth (38). 8-NH2-Ado has previously been associated with a survival program that is initiated because of metabolic dysfunction and this survival program happens alongside the induction of apoptosis (16). In this study, we investigated if p53 function played a part in 8-NH2-Ado-induced cell death. Importantly, we have ...
In recent years we have gained great insight into the molecular pathogenesis of the 5q- syndrome, a distinct subtype of myelodysplasia. The demonstration of haploinsufficiency of the ribosomal gene RPS14 (mapping to the commonly deleted region) and the finding that this is the cause of the erythroid defect in the 5qsyndrome represent major advances. A mouse model of the human 5q- syndrome generated by large-scale deletion of the Cd74-Nid67 interval (containing RPS14) further supports a critical role for RPS14 haploinsufficiency. It is widely accepted that ribosomal deficiency results in p53 activation and defective erythropoiesis and the crossing of the 5q- mice with p53 deficient mice ameliorated the erythroid progenitor defect. Emerging data suggests that the p53 activation observed in the mouse model may also apply to the human 5q- syndrome.
Kondrashov and Koonin (2004) identified 685 haploinsufficient and 422 haplosufficient human genes by searching for diseases with dominant and recessive inheritances, respectively, in the database OMIM (http://www.ncbi.nlm.nih.gov/sites/entrez?db=omim). Because dominance is not necessarily caused by haploinsufficiency and can arise from dominant-negative mutations, we decided to use a better search strategy. We searched OMIM with the terms "haploinsufficiency" and "haploinsufficient" and identified 222 haploinsufficient genes at the time of this study (October 2007). However, we could not search for haplosufficient genes using the terms "haplosufficiency" and "haplosufficient" because the vast majority of genes are haplosufficient and OMIM flags only haploinsufficient genes. Following Kondrashov and Koonin (2004), we identified 780 genes from OMIM by searching for diseases of recessive inheritance. Among them, 51 are known to be haploinsufficient, and the remaining 729 are regarded as ...
The transcriptional programs that guide lymphocyte differentiation depend on the precise expression and timing of transcription factors (TFs). The TF BACH2 is essential for T and B lymphocytes and is associated with an archetypal super-enhancer (SE). Single-nucleotide variants in the BACH2 locus are associated with several autoimmune diseases, but BACH2 mutations that cause Mendelian monogenic primary immunodeficiency have not previously been identified. Here we describe a syndrome of BACH2-related immunodeficiency and autoimmunity (BRIDA) that results from BACH2 haploinsufficiency. Affected subjects had lymphocyte-maturation defects that caused immunoglobulin deficiency and intestinal inflammation. The mutations disrupted protein stability by interfering with homodimerization or by causing aggregation. We observed analogous lymphocyte defects in Bach2-heterozygous mice. More generally, we observed that genes that cause monogenic haploinsufficient diseases were substantially enriched for TFs and SE
To accomplish these aims we will use our well-validated, automated and high-throughput chemogenomic assay, HaploInsufficiency Profiling (HIP), based on our laboratory s observation of "drug-induced haploinsufficiency". Drug-induced haploinsufficiency is the observed growth sensitivity in the presence of a drug of a diploid yeast strain heterozygous for the gene encoding the drug target (Nat Genet 21, March 1999). In our rapid and cost-effective HIP assay, a complete collection of heterozygous deletion strains are pooled, grown in the presence of compound and sampled as a function of time. Molecular bar-codes incorporated into each strain allow parallel analysis and relative strain abundance to be quantitatively assessed either by hybridization to oligonucleotide arrays, or more recently, by Next Generation Sequencing Technologies. The result is a list of genes ranked in order of their importance for growth and survival, a quantitative metric termed "fitness". Strains most sensitive to drug often ...
Background Chromosome 6pter-p24 deletion syndrome (OMIM #612582) is a recognized chromosomal disorder. Most of the individuals with this syndrome carry a terminal deletion of the short arm of...
TY - JOUR. T1 - Munc18-1 haploinsufficiency impairs learning and memory by reduced synaptic vesicular release in a model of Ohtahara syndrome. AU - Orock, Albert. AU - Logan, Sreemathi. AU - Deak, Ferenc. PY - 2018/4. Y1 - 2018/4. N2 - Ohtahara syndrome, also known as type 4 of Early Infantile Epileptic Encephalopathy with suppression bursts (EIEE-4) is currently an untreatable disorder that presents with seizures and impaired cognition. EIEE-4 patients have mutations most frequently in the STXBP1 gene encoding a Sec protein, munc18-1. The exact molecular mechanism of how these munc18-1 mutations cause impaired cognition, remains elusive. The leading haploinsufficiency hypothesis posits that mutations in munc18-1 render the protein unstable leading to its degradation. Expression driven by the healthy allele is not sufficient to maintain the physiological function resulting in haploinsufficiency. The aim of this study has been to understand how munc18-1 haploinsufficiency causes cognitive ...
Diseases caused by gene haploinsufficiency in humans commonly lack a phenotype in mice that are heterozygous for the orthologous factor, impeding the study of complex phenotypes and critically limiting the discovery of therapeutics. Laboratory mice have longer telomeres relative to humans, potentially protecting against age-related disease caused by haploinsufficiency. Here, we demonstrate that telomere shortening in NOTCH1-haploinsufficient mice is sufficient to elicit age-dependent cardiovascular disease involving premature calcification of the aortic valve, a phenotype that closely mimics human disease caused by NOTCH1 haploinsufficiency. Furthermore, progressive telomere shortening correlated with severity of disease, causing cardiac valve and septal disease in the neonate that was similar to the range of valve disease observed within human families. Genes that were dysregulated due to NOTCH1 haploinsufficiency in mice with shortened telomeres were concordant with proosteoblast and ...
TY - JOUR. T1 - Foxf1 haploinsufficiency reduces Notch-2 signaling during mouse lung development. AU - Kalinichenko, Vladimir V.. AU - Gusarova, Galina A.. AU - Kim, Il-man. AU - Shin, Brian. AU - Yoder, Helena M.. AU - Clark, Jean. AU - Sapozhnikov, Alexander M.. AU - Whitsett, Jeffrey A.. AU - Costa, Robert H.. PY - 2004/3/1. Y1 - 2004/3/1. N2 - The forkhead box (Fox) f1 transcription factor is expressed in the mouse splanchnic (visceral) mesoderm, which contributes to development of the liver, gallbladder, lung, and intestinal tract. Pulmonary hemorrhage and peripheral microvascular defects were found in approximately half of the newborn Foxf1(+/-) mice, which expressed low levels of lung Foxf1 mRNA [low-Foxf1(+/-) mice]. Microvascular development was normal in the surviving newborn high-Foxf1(+/-) mice, which compensated for pulmonary Foxf1 haploinsufficiency and expressed wild-type Foxf1 levels. To identify expression of genes regulated by Foxf1, we used Affymetrix microarrays to determine ...
TY - JOUR. T1 - Nedd4 haploinsufficient mice display moderate insulin resistance, enhanced lipolysis, and protection against high-fat diet-induced obesity. AU - Li, Jing Jing. AU - Jr, Robert J.Ferry. AU - Diao, Shiyong. AU - Xue, Bingzhong. AU - Bahouth, Suleiman. AU - Liao, Francesca-Fang. PY - 2015/4/1. Y1 - 2015/4/1. N2 - Neural precursor cell expressed developmentally down-regulated protein 4 (Nedd4) is the prototypical protein in the Nedd4 ubiquitin ligase (E3) family, which governs ubiquitin-dependent endocytosis and/or degradation of plasma membrane proteins. Loss of Nedd4 results in embryonic or neonatal lethality in mice and reduced insulin/IGF-1 signaling in embryonic fibroblasts. To delineate the roles of Nedd4 in vivo, we examined the phenotypes of heterozygous knockout mice using a high-fat diet-induced obesity (HFDIO) model. We observed that Nedd4+/- mice are moderately insulin resistant but paradoxically protected against HFDIO. After high-fat diet feeding, Nedd4+/-mice showed ...
Sakurai, T., Dorr, N. P., Takahashi, N., McInnes, L. A., Elder, G. A. and Buxbaum, J. D. (2011), Haploinsufficiency of Gtf2i, a gene deleted in Williams Syndrome, leads to increases in social interactions. Autism Res, 4: 28-39. doi: 10.1002/aur.169 ...
A20 haploinsufficiency (HA20): clinical phenotypes and disease course of patients with a newly recognised NF-kB-mediated autoinflammatory disease ...
Click figures for larger images - opens in new tab/window). Project 1: Investigate signaling mechanisms of PGRN and its function in the lysosomes. Progranulin (PGRN) is a secreted glycoprotein of 7.5 granulin repeats. PGRN and granulin peptides have been implicated in many processes, including tumorigenesis, diabetes, wound healing, neuronal survival and inflammation. Elevated levels of PGRN have been associated with increased tumorigenesis and invasion. Mutations in PGRN, resulting in PGRN haplo-insufficiency, are a leading cause of frontotemporal lobar degeneration with ubiquitin positive inclusions (FTLD-U). Moreover, human patient with PGRN homozygous mutations develop neuronal ceroid lipofucinosis (NCL), a lysosome storage disorder, suggesting a role of PGRN in regulating lysosomal function. However, how PGRN regulates so many cellular processes are largely unknown. We are interested in the following aspect of PGRN biology:. 1.1 Determine the function of PGRN in the lysosome. We have shown ...
Immature hematopoietic cells from mice with a large segmental deletion found in human myeloid malignancies exhibit cardinal features of myelodysplastic syndrome.
Noggin is a secreted peptide that binds and inactivates Bone Morphogenetic Proteins, members of the transforming growth factor beta superfamily of secreted signaling molecules. In vertebrate limbs, Noggin is expressed in condensing cartilage and immature chondrocytes. Inactivation of the Noggin gene …
ASXL1 is frequently mutated in myeloid malignancies and is known to co-occur with other gene mutations. However, the molecular mechanisms underlying the leukemogenesis associated with ASXL1 and cooperating mutations remain to be elucidated. Here, we report that Asxl1 loss cooperated with haploinsufficiency of Nf1, a negative regulator of the RAS signaling pathway, to accelerate the development of myeloid leukemia in mice. Loss of Asxl1 and Nf1 in hematopoietic stem and progenitor cells resulted in a gain-of-function transcriptional activation of multiple pathways such as MYC, NRAS, and BRD4 that are critical for leukemogenesis. The hyperactive MYC and BRD9 transcription programs were correlated with elevated H3K4 trimethylation at the promoter regions of genes involving these pathways. Furthermore, pharmacological inhibition of both the MAPK pathway and BET bromodomain prevented leukemia initiation and inhibited disease progression in Asxl1Δ/Δ Nf1Δ/Δ mice. Concomitant mutations of ASXL1 and ...
Drug-induced haploinsufficiency of fission yeast provides a powerful tool for identification of drug targets / Jo Young Park; Young Joo Jang; S J You; Young Sook Kil; Eun Jung Kang; Jee Hee Ahn; Young Kwon Ryoo; Min Youn Lee; S Y Park; H J Lee; J Y Kim; S H Kim; W S Yang; K B Song; H M Park; Y J Chung; H B Kim; Kwang Lae Hoe; Kyung Sook Chung; Dong Uk Kim; Hyang Sook Yoo; Mi Sun Won , 2003 ...
In the quest for novel molecular mediators of glioma progression, we studied the regulation of FBXW 7 (hCDC 4/hAGO/SEL 10), its association with survival of patients with glioblastoma and its potential role as a tumor suppressor gene in glioma cells. The F-box protein Fbxw7 is a component of SCFFbxw7, a Skp1-Cul1-F-box E3 ubiquitin ligase complex that tags specific proteins for proteasome degradation. FBXW 7 is mutated in several human cancers and functions as a haploinsufficient tumor suppressor in mice. Any of the identified targets, Cyclin E, c-Myc, c-Jun, Notch1/4 and Aurora-A may have oncogenic properties when accumulated in tumors with FBXW 7 loss. We tested the expression of FBXW 7 in human glioma biopsies by quantitative PCR and compared the transcript levels of grade IV glioma (glioblastoma, G-IV) with those of grade II tumors (G-II). In more than 80% G-IV, expression of FBXW 7 was significantly reduced. In addition, levels of FBXW 7 were correlated with survival indicating a possible
Mutations in the human NBEAL2 gene cause gray platelet syndrome (GPS), a bleeding diathesis characterized by a lack of α granules in platelets. The functions of the NBEAL2 protein have not been explored outside platelet biology, but there are reports of increased frequency of infection and abnormal neutrophil morphology in patients with GPS. We therefore investigated the role of NBEAL2 in immunity by analyzing the phenotype of Nbeal2-deficient mice. We found profound abnormalities in the Nbeal2-deficient immune system, particularly in the function of neutrophils and NK cells. Phenotyping of Nbeal2-deficient neutrophils showed a severe reduction in granule contents across all granule subsets. Despite this, Nbeal2-deficient neutrophils had an enhanced phagocyte respiratory burst relative to Nbeal2-expressing neutrophils. This respiratory burst was associated with increased expression of cytosolic components of the NADPH oxidase complex. Nbeal2-deficient NK cells were also dysfunctional and showed ...
Mutations in the human NBEAL2 gene cause gray platelet syndrome (GPS), a bleeding diathesis characterized by a lack of α granules in platelets. The functions of the NBEAL2 protein have not been explored outside platelet biology, but there are reports of increased frequency of infection and abnormal neutrophil morphology in patients with GPS. We therefore investigated the role of NBEAL2 in immunity by analyzing the phenotype of Nbeal2-deficient mice. We found profound abnormalities in the Nbeal2-deficient immune system, particularly in the function of neutrophils and NK cells. Phenotyping of Nbeal2-deficient neutrophils showed a severe reduction in granule contents across all granule subsets. Despite this, Nbeal2-deficient neutrophils had an enhanced phagocyte respiratory burst relative to Nbeal2-expressing neutrophils. This respiratory burst was associated with increased expression of cytosolic components of the NADPH oxidase complex. Nbeal2-deficient NK cells were also dysfunctional and showed ...
NBEAL1 is a protein that in humans is encoded by the NBEAL1 gene. It is found on chromosome 2q33.2 of Homo sapiens. Through the different domains of this protein, the function of NBEAL1 is predicted to be involved in the following cellular mechanisms: vesicle trafficking, membrane dynamics, receptor signaling, pre-mRNA processing, signal transduction and cytoskeleton assembly. NBEAL1 is also known as Amytorophic Lateral Sclerosis 2 Chromosomal Region, ALS2CR16 and ALS2CR17. The mRNA for this protein consists of 9058 base pairs in a linear sequence with the coding sequence begins at base pair number 334 and extends until base pair number 8418. The translated protein is a total 56 exons that constitute a final length of 2694 amino acids. There are currently 9 known isoforms within humans. Neurobeachin-like1 contains five domains: DUF4704, DUF4800, PH_BEACH, Beach, and WD40 repeats. DUF4704 is a domain of unknown function. While the function of this domain is unknown, it is conserved within ...
We report that Il4-hemizygous mice exhibited severely compromised IgE responses but not IgG responses against OVA or hapten in OVA/Alum or hapten-OVA/Alum immunization models. Serum OVA or hapten-specific IgE was diminished by 10-100 fold in Il4-hemizygous mice, 6-fold fewer hapten-specific IgE ASC were generated, and hapten-specific IgE levels on mast cells and basophils were reduced 3-10 fold following immunization of Il4-hemizygous mice. The reduced levels of IL-4 produced by in vitro restimulated IL-4G4/+ CD4+ T cells from allergen-immunized Il4-hemizygous mice supports the notion that it is the reduced amount of IL-4 produced by the lymph node CD4+ T cell compartment that leads to the IgE deficiency.. In addition to reduced IgE production, Il4-hemizygous mice were also protected from IgE-dependent oral allergen-induced diarrhea, but remained susceptible to i.v.-induced Ab-mediated active systemic anaphylaxis. Given that both the production of IgE and mastocytosis is a necessary step for ...
Nineteen patients with deletions in chromosome 6p22-p24 have been published so far. The syndromic phenotype is varied, and includes intellectual disability, behavioural abnormalities, dysmorphic features and structural organ defects. Heterogeneous deletion breakpoints and sizes (1-17 Mb) and overlapping phenotypes have made the identification of the disease causing genes challenging. We suggest JARID2 and ATXN1, both harbored in 6p22.3, as disease causing genes. We describe five unrelated patients with de novo deletions (0.1-4.8 Mb in size) in chromosome 6p22.3-p24.1 detected by aCGH in a cohort of approximately 3600 patients ascertained for neurodevelopmental disorders. Two patients (Patients 4 and 5) carried non-overlapping deletions that were encompassed by the deletions of the remaining three patients (Patients 1-3), indicating the existence of two distinct dosage sensitive genes responsible for impaired cognitive function in 6p22.3 deletion-patients. The smallest region of overlap (SRO I) in
Maturity-onset diabetes of the young (MODY) is a subtype of diabetes characterized by early age of onset (usually ,25 years), autosomal dominant inheritance, and a progressive defect in β-cell function (1). In U.K. populations, mutations in the hepatocyte nuclear factor-1α (HNF-1α) gene account for ∼65% of cases (2). Over 120 different HNF-1α mutations have been reported (3), of which ∼30% are nonsense or frameshift and lead to the production of premature termination codons (PTCs) (4). The most common HNF-1α mutation results from the insertion of a C nucleotide in a polyC tract in exon 4 (2,5-7). This mutation, P291fsinsC, accounts for ∼20% of families with HNF-1α mutations (4,8,9).. HNF-1α mutations might produce the MODY phenotype by haploinsufficiency or a dominant-negative mutational mechanism. There is considerable support for haploinsufficiency; a mutation in the HNF-1α promoter that disrupts the HNF-4α binding site results in a phenotype indistinguishable from mutations in ...
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More over, the dysregulated miRNAs showed consistent trends in all three of the PGRN FTLD TDP subtypes compared to PGRN FTLD TDP patients, suggesting the miRNA candidates we identified are unique to PGRN haploinsufficiency. In further support that the miRNAs dysregulated in our array and validation studies are under the control of systemic PGRN mediated mechan isms, we found that 5 miRNAs were also upre gulated in the cerebellum of PGRN FTLD TDP com pared to PGRN FTLD TDP patients. To further study the five candidate miRNAs, we silenced PGRN expression in SH SY5Y cells, however, none of the 3 miRNAs detectable in SY SY5Y cells dis played a significant difference in expression between con trol and PGRN silenced cells. This finding suggests that long term knockdown of PGRN may be necessary, con sistent with the late onset of symptoms in human FTLD patients.. The mechanism by which PGRN haploinsufficiency in FTLD patients leads to altered miRNA expression is currently unclear and requires future ...
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73.National Toxicol Program. NTP report on the toxicology studies of aspartame (CAS No. 22839-47-0) in genetically modified (FVB Tg.AC hemizygous) and B6.129-Cdkn2atm1Rdp (N2) deficient mice and carcinogenicity studies of aspartame in genetically modified [B6.129-Trp53tm1Brd (N5) haploinsufficient] mice (feed studies). 2005. Beschikbaar via: http://www.ncbi.nlm.nih.gov/pubmed/18685711. Geraadpleegd op 09-09- ...
22839-47-0) in Genetically Modified (FVB Tg.AC Hemizygous) and B6.129-Cdkm2atn1Rdp (N2) Deficient Mice and Carcinogenicity Studies of Aspartame in Genetically Modified [B6.129-Trp53tm1Brd (N5) Haploinsufficient] Mice (Feed Studies ...
several low-copy repeats, recently associated with a 900 kb inversion present in up to 20 percent of European subjects, are present in 17q21.31; this inversion is present in all examined parent originating the deletion ; the deleted region contains the MAPT gene, implicated in late onset neurodegenerative disorders, and other genes; haploinsufficiency of KANSL1 is sufficient to cause the classical 17q21.31 microdeletion syndrome phenotype PMID: 22544367,, PMID: 22544363 ...
As a major regulator of EMT, ZEB1 is capable of acting as either a transcriptional activator or repressor and aberrant expression of ZEB1 is associated with tumorigenesis and disease.19,37-40 During EMT, the expression of CDH1, a classic epithelial marker that is involved in cell-cell adhesion and in the maintenance of apicobasal polarity, is repressed by ZEB1 via its binding to two E2 box motifs in the CDH1 promoter region.29,30 Although altered ZEB1 levels have been shown to affect CDH1 expression, we have demonstrated that the CDH1 transcript is not present in ex vivo human corneal endothelial cells (and presumably also absent in in vivo endothelium).41-43 Therefore, ZEB1 haploinsufficiency likely results in changes in the expression of other genes that are the direct targets of ZEB1 in the corneal endothelium. Although it has not yet been definitively determined which of these differentially expressed genes are involved in the pathogenesis of PPCD, altered expression of type IV collagens, ...
J:75787 Kalinichenko VV, Zhou Y, Bhattacharyya D, Kim W, Shin B, Bambal K, Costa RH, Haploinsufficiency of the Mouse Forkhead Box f1 Gene Causes Defects in Gall Bladder Development. J Biol Chem. 2002 Apr 5;277(14):12369-74 ...
R, this data suggests that Mtap may be acting in a haploinsufficient manner. To develop evidence that germline heterozygosity for Mtap can have phenotypic
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TY - JOUR. T1 - Ablepharon and craniosynostosis in a patient with a localized TWIST1 basic domain substitution. AU - Takenouchi, Toshiki. AU - Sakamoto, Yoshiaki. AU - Sato, Hironori. AU - Suzuki, Hisato. AU - Uehara, Tomoko. AU - Ohsone, Yoshiteru. AU - Kosaki, Kenjiro. PY - 2018/1/1. Y1 - 2018/1/1. N2 - The TWIST family is a group of highly conserved basic helix-loop-helix transcription factors. In humans, TWIST1 haploinsufficiency causes Saethre-Chotzen syndrome, which is characterized by craniosynostosis. Heterozygous localized TWIST1 and TWIST2 basic domain substitutions exert antimorphic effects to cause Sweeney-Cox syndrome, Barber-Say syndrome, and ablepharon-macrostomia syndrome, respectively. Sweeney-Cox syndrome, Barber-Say syndrome, and ablepharon-macrostomia syndrome share the facial features of ablepharon, hypertelorism, underdevelopment of the eyelids, and cheek pads adjacent to the corners of the mouth. Existence of phenotypic overlap between Saethre-Chotzen syndrome and ...
Using a wide array of morphological and functional assays, we determined that defects in the lymphatic vasculature of Prox1+/- mice precede the onset of obesity, which develops as these animals age. Prox1 conditional deletion in LECs (Lyve1+/GFPCre;Prox1+/Flox) showed a similar phenotype to those in standard Prox1 heterozygous mice, including edema at embryonic stage E14.5, chylous ascites, reduced viability, and reduced ear lymph flow; however, the reduced postnatal viability of these conditional mice makes it very difficult to have access to a significant number of adult mice. We believe that this reduced viability is because the Lyve1+/GFPCre strain used for these crosses is not yet in the pure NMRI background necessary for Prox1+/- mouse survival. Importantly, we also showed that restoring Prox1 levels in Prox1+/- LECs was sufficient to rescue the lymphatic defects in Prox1+/- mice and that Lyve1+/GFPCre;Jojo-Prox1;Prox1+/- mice had an almost normal neonatal survival rate, did not exhibit ...
PubMedID: 23300014 | NR2F1 haploinsufficiency is associated with optic atrophy, dysmorphism and global developmental delay. | American journal of medical genetics. Part A | 2/1/2013
We describe simple behavior tests that are sensitive to lithium and show that deletion of one copy of the Gsk-3β gene mimics the effect of lithium on these behaviors. Molecular targets of GSK-3, including β-catenin, are also affected similarly by lithium and Gsk-3β haploinsufficiency. These behavioral and molecular correlations strongly support the hypothesis that GSK-3 is an important target for the behavioral effects of lithium.. Lithium decreases time immobile in the FST in a robust, dose-dependent manner. To our knowledge, an effect of chronic lithium in the FST has not been reported. Lithium does not affect time immobile for rats in the FST (Hata et al., 1995; Kitamura et al., 2002; Einat et al., 2003; Wegener et al., 2003). Acute lithium injection has been reported to reduce time immobile in mice if animals are tested 30 min after injection but not at 45 min (Nixon et al., 1994; Redrobe and Bourin, 1999a). Acute lithium also reportedly enhances the effect of antidepressants on the FST ...
In Drosophila embryos, checkpoints maintain genome stability by delaying cell cycle progression that allows time for damage repair or to complete DNA synthesis. Drosophila MOF, a member of MYST histone acetyl transferase is an essential component of male X hyperactivation process. Until recently its involvement in G2/M cell cycle arrest and defects in ionizing radiation induced DNA damage pathways was not well established. Drosophila MOF is highly expressed during early embryogenesis. In the present study we show that haplo-insufficiency of maternal MOF leads to spontaneous mitotic defects like mitotic asynchrony, mitotic catastrophe and chromatid bridges in the syncytial embryos. Such abnormal nuclei are eliminated and digested in the yolk tissues by nuclear fall out mechanism. MOF negatively regulates Drosophila checkpoint kinase 2 tumor suppressor homologue. In response to DNA damage the checkpoint gene Chk2 (Drosophila mnk) is activated in the mof mutants, there by causing centrosomal inactivation
Consistent with expectations, we have shown that in the mouse model of collagen III haploinsufficiency chronic MMP inhibition by doxycycline treatment prevented increased MMP activity in the carotid artery and the skin present in untreated HT mice. The normalization of MMP activity was accompanied by partial normalization of collagen content in the tunica media of the abdominal aorta in HT mice. This mild increase in collagen accumulation seems to be sufficient to strengthen the vessel, because the increase in stress-induced vessel pathology in untreated HT mice was prevented by doxycycline treatment. Therefore, on the basis of these results, doxycycline therapy might be considered as a treatment for vEDS, at least of the haploinsufficient type.. The rationale for the only available preventive strategy for vEDS by β1-AR blocker was mainly mechanical, to reduce the arterial wall stress by controlling the rate of increase of pressure over time in the pulse wave (dP/dt) and thus to reduce "wearing ...
The results of this study indicate that a defect in the MMR machinery unmasks a strong gene dosage effect for ATR in the regulation of cell‐cycle checkpoint functions, chromosome dynamics, and tumor suppression. As ATR expression is required for viability is cycling cells (Brown and Baltimore, 2000; de Klein et al, 2000), biallelic inactivation of ATR may not be tolerated, even in late‐stage malignant cells. However, the present findings demonstrate that ATR haploinsufficiency leads to high‐level genetic instability and accelerated tumorigenesis in MMR‐deficient hosts. This mechanism may explain the appearance of heterozygous mutations in ATR in gastric and endometrial cancers bearing the MSI phenotype (Menoyo et al, 2001; Vassileva et al, 2002). Our results suggest that such cancers are haploinsufficient for ATR function, and that monoallelic ATR gene inactivation is positively selected during tumor evolution, since this event fuels genetic instability and tumor progression.. The ...
Although it is likely that chromosomal deletions occur randomly, those that result in a proliferative advantage or resistance to, e.g., physiological apoptosis could initiate clonal outgrowth. Selection for clones with a specific region of LOH could be related to a somatic or germline loss of a wild-type allele, resulting in hemizygosity for an SNP-encoded, disease-prone allele or a somatic or germline mutated allele (Fig. 1). If the affected area includes promoters of alleles that are differentially silenced (imprinted), deletion can lead to either a gain of imprinting (GOI) or loss of imprinting (LOI). This can result in changes in gene expression. UPD can also lead to the duplication of an imprinted expressed allele or a silenced (methylated), imprinted allele. When the transcription of both alleles is required for normal cellular physiology, deletions can result in pathological haploinsufficiency, and thus LOH is less likely to play a pathogenic role (Fig. 1).. There are similarities and ...
Control of inflammation critically depends on the twist genes. Genetic haploinsufficiency of both twist1 and twist2 results in fatal systemic inflammatory immunopathology in mice, which die before day 14 (4). In this study, we show that twist1 is expressed in Th1 EM cells. Its expression is induced by IL-12 via STAT4 and TCR signaling, activating NFAT and NF-κB. Expression of twist1 follows TCR stimulation transiently and increases upon repeated stimulation. Thus, imprinting for enhanced twist1 expression is a hallmark of repeatedly restimulated Th1 memory cells.. The proximal promoter of twist1 contains phylogenetically conserved binding sites for NFAT, NF-κB, and STAT proteins. Both NFAT and NF-κB have to bind to the promoter of twist1 in Th cells to induce expression, i.e., twist1 is expressed only by activated Th cells. In the initial activation of naive Th cells, NFAT and NF-κB cannot induce transcription of twist1 on their own, but require concerted binding of activated STAT4 to the ...