A second locus for very-late-onset Alzheimer disease: a genome scan reveals linkage to 20p and epistasis between 20p and the amyloid precursor protein region.
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We used a covariate-based linkage method to reanalyze genome scan data from affected sibships collected by the Alzheimer Disease (AD) Genetics Initiative of the National Institute of Mental Health. As reported in an earlier article, the amyloid-beta precursor protein (APP) region is strongly linked to affected sib pairs of the oldest current age (i.e., age either at last exam or at death) who lack E4 alleles at the apolipoprotein E (ApoE) locus. We now report that a region on 20p shows the same pattern. A model that includes current age and the number of E2 alleles as covariates gives a LOD score of 4.1. The signal on 20p is near the location of the gene coding for cystatin-C, previously shown to be associated with late-onset AD and to codeposit with APP in the brains of patients with AD. Two-locus analysis provides evidence of strong epistasis between 20p and the APP region, limited to the oldest age group and to those lacking ApoE4 alleles. We speculate that high-risk polymorphisms in both regions produce a biological interaction between these two proteins that increases susceptibility to a very-late-onset form of AD. (+info)
Cloning and characterization of PAK5, a novel member of mammalian p21-activated kinase-II subfamily that is predominantly expressed in brain.
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The p21-activated kinase (PAK) family of protein kinases has recently attracted considerable attention as an effector of Rho family of small G proteins and as an upstream regulator of MAPK signalling pathways during cellular events such as re-arrangement of the cytoskeleton and apoptosis. We have cloned a novel human PAK family kinase that has been designated as PAK5. PAK5 contains a CDC42/Rac1 interactive binding (CRIB) motif at the N-terminus and a Ste20-like kinase domain at the C-terminus. PAK5 is structurally most related to PAK4 and PAK6 to make up the PAK-II subfamily. We have shown that PAK5 preferentially binds to CDC42 in the presence of GTP and that CRIB motif is essential for this interaction. PAK5 is a functional protein kinase but unlike PAK-I family kinases (PAK1, 2, and 3), the kinase activity of PAK5 does not seem to require the binding of CDC42. Overexpression of PAK5 activates the JNK kinase pathway but not p38 or ERK pathways. PAK5 transcript is predominantly expressed in brain as revealed by Northern blot and in situ hybridization. The expression pattern of PAK5 is distinct from that of PAK4 and PAK6, suggesting a functional division among PAK-II subfamily kinases based on differential tissue distribution. (+info)
Comprehensive analysis of amino acid and nucleotide composition in eukaryotic genomes, comparing genes and pseudogenes.
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Based on searches for disabled homologs to known proteins, we have identified a large population of pseudogenes in four sequenced eukaryotic genomes-the worm, yeast, fly and human (chromosomes 21 and 22 only). Each of our nearly 2500 pseudogenes is characterized by one or more disablements mid-domain, such as premature stops and frameshifts. Here, we perform a comprehensive survey of the amino acid and nucleotide composition of these pseudogenes in comparison to that of functional genes and intergenic DNA. We show that pseudogenes invariably have an amino acid composition intermediate between genes and translated intergenic DNA. Although the degree of intermediacy varies among the four organisms, in all cases, it is most evident for amino acid types that differ most in occurrence between genes and intergenic regions. The same intermediacy also applies to codon frequencies, especially in the worm and human. Moreover, the intermediate composition of pseudogenes applies even though the composition of the genes in the four organisms is markedly different, showing a strong correlation with the overall A/T content of the genomic sequence. Pseudogenes can be divided into 'ancient' and 'modern' subsets, based on the level of sequence identity with their closest matching homolog (within the same genome). Modern pseudogenes usually have a much closer sequence composition to genes than ancient pseudogenes. Collectively, our results indicate that the composition of pseudogenes that are under no selective constraints progressively drifts from that of coding DNA towards non-coding DNA. Therefore, we propose that the degree to which pseudogenes approach a random sequence composition may be useful in dating different sets of pseudogenes, as well as to assess the rate at which intergenic DNA accumulates mutations. Our compositional analyses with the interactive viewer are available over the web at http://genecensus.org/pseudogene. (+info)
Maturity-onset diabetes of the young caused by a balanced translocation where the 20q12 break point results in disruption upstream of the coding region of hepatocyte nuclear factor-4alpha (HNF4A) gene.
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Monogenic human disorders have been used as paradigms for complex genetic disease and as tools for establishing important insights into mechanisms of gene regulation and transcriptional control. Maturity-onset diabetes of the young (MODY) is a monogenic dominantly inherited form of diabetes that is characterized by defective insulin secretion from the pancreatic beta-cells. A wide variety of mutation types in five different genes have been identified that result in this condition. There have been no reports of a chromosome deletion or translocation resulting in MODY. We report a pedigree where MODY cosegregates with a balanced translocation [karyotype 46, XX t(3;20) (p21.2;q12)]. The chromosome 20 break point, 20q12, is within the region of one of the known MODY genes, hepatocyte nuclear factor-4alpha (HNF4A). Fluorescence in situ hybridization analysis demonstrated that the break point does not disrupt the coding region of this gene, but it lies at least 6 kb upstream of the conventional promoter (P1). We propose that this mutation disrupts the spatial relationship between the recently described alternate distal pancreatic promoter (P2) and HNF4A. This is the first case of MODY due to a balanced translocation, and it provides evidence to confirm the crucial role of an upstream regulator of HNF4A gene expression in the beta-cell. (+info)
First genomic localization of oculo-oto-dental syndrome with linkage to chromosome 20q13.1.
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PURPOSE: To characterize the phenotype of autosomal dominant oculo-oto-dental (OOD) syndrome, map the disease locus in a five-generation British family, and evaluate a candidate gene. METHODS: Full clinical assessments in all affected patients included slit lamp and retina examination, refraction, A-scan ultrasound, audiograms, and dental assessments. Genomic DNA from all family members was genotyped, by polymerase chain reaction, for polymorphic genetic markers covering the entire genome. Two-point LOD scores were generated using a linkage analysis suite of computer programs. The gene for eyes absent 2 (EYA2) was screened for mutations by direct automated sequencing and Southern blot analysis. RESULTS: All the affected individuals examined had iris and retina coloboma associated with high-frequency, progressive, sensorineural deafness and globodontia. This is the only genetic disease known to result in pathologically enlarged teeth. The locus for OOD (OOD1) was mapped to 20q13.1. A maximum two-point LOD score of 3.31 was obtained with marker locus D20S836 at a recombination fraction of theta; = 0.00. Two critical recombinations in the pedigree positioned this locus to a region flanked by marker loci D20S108 and D20S159, giving a critical disease interval of 12 centimorgans (cM). Mutation screening of one candidate gene, EYA2, revealed no disease-associated mutations or polymorphic variants. CONCLUSIONS: This is the first genetic localization for the OOD phenotype (ODD1). The disease-causing gene is localized within a 12-cM critical region of chromosome 20q13.1. The identification of the disease gene is not only relevant to the study of vision and hearing defects, but also highlights an exceptional gene involved in the development of human dentition. (+info)
Medical genetics: 2. The diagnostic approach to the child with dysmorphic signs.
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Dysmorphology is the branch of clinical genetics in which clinicians and researchers study and attempt to interpret the patterns of human growth and structural defects. Reaching an accurate diagnosis for children with dysmorphic signs is important to their families, because it makes available all the accumulated knowledge about the relevant condition and may provide the family with the opportunity for interaction with patient or parent support groups. I show in this review that reaching a diagnosis in dysmorphology involves an approach that is not fundamentally different from that of other medical disciplines. Cytogenetic and molecular techniques continue to improve our ability to make precise syndrome diagnoses; however, these tests are expensive and should be used selectively. (+info)
A locus on human chromosome 20 contains several genes expressing protease inhibitor domains with homology to whey acidic protein.
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A locus containing 14 genes, encoding protein domains that have homology with whey acidic protein (WAP), has been identified in a region of 678 kb on human chromosome 20q12-13.1. Among them are genes of the known or postulated protease inhibitors elafin, secretory leucocyte protease inhibitor, human epididymis gene product 4, eppin, and huWAP2. Nucleotide sequences of full-length transcripts were obtained from cDNA fragments generated by rapid amplification of cDNA ends. Characteristic features of the genes are that the upstream promoter regions are devoid of TATA-boxes and that the coding nucleotides are divided into distinct exons for the signal peptide and for each WAP domain. In most cases, there is also a separate exon encompassing a few terminal codons and the 3' untranslated nucleotides. There are also examples of mixed type inhibitors, that encode inhibitor domains of both WAP and Kunitz types. Several of the genes appear to be expressed ubiquitously, but, in most cases, the highest transcript levels are found in epididymis followed by testis and trachea. Some of the genes also display high transcript levels in neural tissues. Potential biological roles of protein products could be in host defence against invading micro-organisms or in the regulation of endogenous proteolytic enzymes, of which those originating from the kallikrein gene locus on chromosome 19 are of particular interest. (+info)
Epilepsy and ring chromosome 20: case report.
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We present the clinical, electroencephalographic, neuroimaging (brain magnetic resonance image - MRI and spectroscopy by MRI) and cytogenetic findings of a young male patient with a rare cytogenetic anomaly characterised by a de novo 46,XY,r(20)(p13q13.3) karyotype. He presents with mental retardation, emotional liability, and strabismus, without any other significant dysmorphies. There are brain anomalies characterised by corpus callosum, uvula, nodule and cerebellum pyramid hypoplasias, besides arachnoid cysts in the occipital region. He had seizures refractory to pharmacotherapy and long period of confusional status with or without a motor component. The authors recognised that the EEG pattern was not fixed but changed over time, specially for bursts of slow waves with great amplitude accompanied or not by sharp components, and bursts of theta waves sharply contoured. Previously, epilepsy solely has been assigned to region 20q13. However, the important structural cerebral alterations present in our case has not been reported associated to such chromosomal abnormality and may indicate possible new chromosomal sites where such atypical neurological characteristics could be mapped. (+info)