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Query: UMLS:C0751781 (NOD)
 6,696 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Trinucleotide repeats at five disease loci (DM, DRPLA, HD, SBMA and SCA1) were surveyed in phenotypically normal individuals from three continental populations. This is the first analysis to examine the population dynamics of these five disease-related trinucleotide repeats in the same individuals from worldwide populations. Roughly half of all alleles observed at each locus are shared between all continental groups. For three loci, disease prevalence in each population corresponds with the number of alleles in the upper tail of the allele-size distribution. The allele-size distributions of African, Asian and Caucasian groups show a high degree of variation, and gene diversity estimates for trinucleotide repeat loci exceed estimates derived from dinucleotide or tetranucleotide repeats. Analyses that compared infinite alleles and stepwise mutation models suggest that normal variation at trinucleotide loci is not generated by stepwise mutation alone. Trees constructed for subpopulations using trinucleotide repeat loci show accurate continental clustering. Interpopulation genetic distance estimates show remarkable similarity to distance estimates produced from tetranucleotide repeats or nuclear restriction site polymorphisms. This finding is especially noteworthy in light of the fact that trinucleotide repeat polymorphisms at these loci can cause disease, while restriction site and tetranucleotide polymorphisms appear to be selectively neutral. In contrast, genetic distance estimates from trinucleotide loci are poorly correlated with genetic distance estimates from mitochondrial sequence data.
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PMID:Population genetics of trinucleotide repeat polymorphisms. 854 30

X-linked recessive bulbospinal neuronopathy (SBMA) is an adult onset motor neuronopathy with androgen receptor (AR) gene mutation of expanded CAG repeat size in the first exon. The size of CAG repeats in the AR gene is one of the determinant factors of the severity and progression rate of SBMA phenotypes, but the meiotic and somatic instability of CAG repeats is far more stable as compared with other diseases caused by trinucleotide repeat expansions such as HD, DRPLA, MJD and SCA1. Several evidences suggest that aberrant transcriptional activity of androgen through mutant AR is related to the pathogenic mechanism of this disease.
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PMID:X-linked recessive bulbospinal neuronopathy (SBMA). 872 92

We have screened a rat brain library to identify proteins which interact with the 5'-end of huntingtin (amino acids 1-171), including the polyglutamine tract, in the yeast two-hybrid system. We detected an interaction with cystathionine beta-synthase (CBS) [L-serine hydrolyase (adding homocysteine), EC 4.2.1.22], which was confirmed in vitro using His-tagged CBS expressed in Escherichia coli , which was able to specifically bind both rat and human full-length huntingtin. Neither normal nor expanded polyglutamine repeat alone interacted with CBS in the yeast two-hybrid system and nor did constructs containing SBMA or DRPLA with normal or expanded polyglutamine tracts. CBS therefore appears to bind specifically to huntingtin. CBS deficiency is associated with homocystinuria, which is known to affect various physiological systems, including the central nervous system. Homocysteine, one of the substrates of CBS, is known to accumulate in homocystinuria and is metabolized to homocysteate and homocysteine sulphinate, both known to be powerful excitotoxic amino acids. It has been suggested that Huntington's disease involves the action of excitotoxic amino acids and this interaction with CBS may suggest a mechanism for such excitotoxic damage.
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PMID:Huntingtin interacts with cystathionine beta-synthase. 946 92

The history of polyglutamine diseases dates back approximately 20 years to the discovery of a polyglutamine repeat in the androgen receptor of SBMA followed by the identification of similar expansion mutations in Huntington's disease, SCA1, DRPLA, and the other spinocerebellar ataxias. This common molecular feature of polyglutamine diseases suggests shared mechanisms in disease pathology and neurodegeneration of disease specific brain regions. In this review, we discuss the main pathogenic pathways including proteolytic processing, nuclear shuttling and aggregation, mitochondrial dysfunction, and clearance of misfolded polyglutamine proteins and point out possible targets for treatment.
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PMID:From pathways to targets: understanding the mechanisms behind polyglutamine disease. 2530 20