Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Huntington's disease (HD) is an inherited, neurodegenerative disorder caused by expansion of a CAG repeat in the IT15 gene, leading to an expanded glutamine repeat in the HD protein. The mechanism by which the expanded repeat causes expression of the disease is not known, though there do not appear to be changes in the mRNA levels. We have conducted quantitative Western blot analyses of HD patients and controls. Expression of the IT15 protein is essentially equal in control and HD frontal cortex. In caudate from HD patients, IT15 protein is decreased in parallel with the decrease in a neuronal marker, suggesting that loss of IT15 protein is secondary to neuronal loss. In order to determine expression of the two alleles of the IT15 protein we used Western blots of 4% polyacrylamide gels. Both alleles of the IT15 protein were expressed at similar levels in HD lymphoblastoid cell lines and HD post-mortem hippocampus and cerebellum (regions relatively spared in HD), indicating that even very long CAG repeats can be translated into polyglutamine. In contrast, in cerebral cortex and caudate (regions severely affected in HD), in the longer expanded repeat cases the expanded allele of the IT15 protein was present at a significantly lower level (compared with the normal length allele), often with a smear of more slowly migrating reactivity above it. These data suggest the possibility of altered structure, abnormal processing or abnormality of protein-protein interactions involving the IT15 protein with the expanded glutamine repeat.
Hum Mol Genet 1995 Aug
PMID:Expression of the Huntington's disease (IT15) protein product in HD patients. 758 75

Two sources of variation in the huntingtin gene, the length of the CCG-rich segment downstream to the (CAG)n stretch undergoing expansion in Huntington disease (HD) and the deletion of 3 bp at codon positions 2642-2645 (delta 2642), were analysed on the normal and HD chromosomes of 80 Italian families affected with HD. No instances of meiotic instability of the CCG-rich segment were detected. A strong linkage disequilibrium was found between the HD mutation and alleles at both polymorphic regions: CCG-rich length alleles different from 176 bp are underrepresented while delta 2642 is overrepresented on HD chromosomes. The presence of such alleles on HD chromosomes does not affect age at onset of the disease. Normal chromosomes displayed a non-random association, shorter (CAG)n segments being preferentially followed by longer CCG-rich segments. Finally, the finding, among normal subjects, of carriers of variants on both chromosomes denotes that variation at either of the two polymorphisms does not impair the function of the huntingtin gene product.
Hum Mol Genet 1994 Jul
PMID:Polymorphism analysis of the huntingtin gene in Italian families affected with Huntington disease. 798 82

The recent identification of the Huntington's disease (HD) gene, enabled us to synthesize oligopeptides corresponding with the carboxy-terminal end of the predicted HD-gene (IT15) product. Immunobiochemcial studies with polyclonal antibodies directed against this synthetic peptide (position 3114-3141) on lymphoblastoid cells from normal individuals and patients with Huntington disease, revealed the presence of a protein (huntingtin) with a molecular mass of approximately 330 kDa. Immunocytochemical studies showed a cytoplasmic localization of huntingtin in various cell types including neurons. In most of the neuronal cells the protein was also present in the nucleus. No difference in molecular mass or intracellular localization was found between normal and mutant cells.
Hum Mol Genet 1993 Dec
PMID:Characterization and localization of the Huntington disease gene product. 811 75

The CCG rich sequence immediately 3' to the CAG repeat that is expanded in Huntington's disease (HD) has recently been shown to be polymorphic with at least 4 alleles differing by multiples of 3 bp being found in the normal population. We have studied the allele distribution in 180 HD families resident in Scotland and have found very strong evidence for disequilibrium in this population. For the 131 families where phase was unambiguously determined, 130 were shown to have a CCG repeat allele of 176 bp cosegregating with the HD chromosome. This observation is significantly different to the normal population distribution where 31% of people have an allele of 185 bp. The evidence for and against a possible founder effect in the Scottish HD population is discussed. We propose the hypothesis that we may have identified a region of the IT15 gene that is critical in Huntington's disease.
Hum Mol Genet 1994 Jan
PMID:A single allele from the polymorphic CCG rich sequence immediately 3' to the unstable CAG trinucleotide in the IT15 cDNA shows almost complete disequilibrium with Huntington's disease chromosomes in the Scottish population. 816 20

150 subjects affected with HD and 45 at high risk for the disease were typed for the CAG trinucleotide repeat at the 5' end of IT15. In all of them we find expanded segments showing marked instability upon transmission. Their length distribution matches those previously reported and inversely correlates (-0.686) with age at onset. Two at risk sibs from a large HD pedigree show expanded segments that overlap the normal distribution and can represent reductions from the HD to the normal range. A case of instability on a normal chromosome is also reported. Finally, an analysis of the CAG repeat as a function of three polymorphic DNA markers at D4S127 and D4S95 loci shows no significant difference in the average repeat length on HD chromosomes grouped according to the cosegregating allele of each marker or to the corresponding haplotype. Despite the marked heterogeneity in repeat length among HD families, haplotypes are not associated with different values around which the repeat length fluctuates.
Hum Mol Genet 1994 Jan
PMID:Analysis of the trinucleotide repeat expansion in Italian families affected with Huntington disease. 816 59

IT15 is a novel gene, localized to chromosome 4, and encoding a protein named Huntingtin. A polymorphic CAG repeat in the proposed open reading frame of IT15 has been characterized, and an elongation of this repeat has been correlated to Huntington's Disease. We have investigated the CAG repeat in the Huntingtin gene in 71 unrelated Danish patients with Huntington's Disease, and found repeat lengths of 39 to 70 repeat units in contrast to 9 to 30 CAG's on normal chromosomes. Comparison of repeat length and age at onset of disease symptoms in 52 individuals indicates an inverse correlation between the age at onset and the number of CAG repeat units.
Hum Mol Genet 1993 Sep
PMID:Trinucleotide repeat elongation in the Huntingtin gene in Huntington disease patients from 71 Danish families. 824 74

The Huntington's Disease (HD) Collaborative Research Group has recently published the sequence of a new cDNA, IT15, containing a polymorphic trinucleotide (CAG)n repeat that is expanded and unstable on HD chromosomes. There is a correlation between the repeat size and the age of onset of symptoms. The suggested polymerase chain reaction (PCR) assay of the (CAG)n repeat requires unusual reaction components and primer concentrations and the use of 5% polyacrylamide sequencing gels to resolve the amplification products. We present a simple PCR assay that produces a smaller product using standard reaction conditions. This gives better resolution of the (CAG)n expansion observed on HD chromosomes by acrylamide gel electrophoresis and allows sufficient product to be obtained to perform assays using agarose gels. This will allow diagnostic labs to do rapid and accurate presymptomatic testing of HD in high risk families.
Mol Cell Probes 1993 Jun
PMID:A new polymerase chain reaction (PCR) assay for the trinucleotide repeat that is unstable and expanded on Huntington's disease chromosomes. 836 69

Mapping genes for nonsyndromic hereditary hearing impairment may lead to identification of genes that are essential for the development and preservation of hearing. We studied a family with autosomal dominant, progressive, low frequency sensorineural hearing loss. Linkage analysis employing microsatellite polymorphic markers revealed a fully linked marker (D4S126) at 4p16.3, a gene-rich region containing IT15, the gene for Huntington's disease (HD). For D4S126, the logarithm-of-odds (lod) score was 3.64 at theta = 0, and the overall maximum lod score was 5.05 at theta = 0.05 for D4S412. Analysis of recombinant individuals maps the disease gene to a 1.7 million base pair (Mb) region between D4S412 and D4S432. Genes for two types of mutant mice with abnormal cochleovestibular function, tilted (tlt) and Bronx waltzer (bv), have been mapped to the syntenic region of human 4p16.3 on mouse chromosome 5. Further studies with the goals of cloning a gene for autosomal nonsyndromic hearing impairment and identifying the murine homologue may explain the role of this gene in the development and function of the cochlea.
Hum Mol Genet 1995 Oct
PMID:A gene for autosomal dominant nonsyndromic hereditary hearing impairment maps to 4p16.3. 859 23

Huntington disease (HD) is an autosomal-dominant disorder of mid-life onset characterized by chorea, dementia, and oculomotor disturbances. Anticipation is commonly seen in HD families, particularly when the disease is inherited through the father. The disorder is associated with an expanded (CAG)n repeat in the IT15 gene that is unstable and tends to increase in size during meiotic transmissions, particularly of paternal origin. We have detected an unusual form of HD on the island of Crete which has distinctly different characteristics. Data from eight families encompassing 48 HD patients, showed a median age at onset 15-20 years later than that for HD occurring worldwide. There is no juvenile cases and no anticipation. DNA analysis in 12 HD patients showed expansion of the (CAG)n repeat the size of which was identical among members of each family or varied by only one unit. The elongated DNA segment was passed stably or contracted during both paternal and maternal transmissions thus indicating that unique molecular mechanisms may be operational in this form of HD.
Hum Mol Genet 1995 Dec
PMID:Stability of the Huntington disease (CAG)n repeat in a late onset form occuring on the Island of Crete. 863 93

Positional cloning has shown that the Huntington disease (HD) mutation is an expanded trinucleotide repeat in the IT15 gene. Although this mutation clearly produces the HD phenotype, the function of the Huntington disease protein remains undefined. One recent immunocytochemical study suggested that the IT15 protein preferentially localizes to the nucleus of affected neuronal cells. If this result is accurate, it could link the biochemical function of this protein to nuclear activities such as gene regulation. To examine the nuclear transport of the Huntington disease protein, we searched for basic peptide motifs that could produce nuclear localization. One peptide (RRKGKEK) was identified that is highly homologous to a consensus nuclear localization signal. When fused to the cytoplasmic reporter protein, beta-galactosidase, nuclear localization was observed in stably transformed human cell lines. In a complementary study, an anti-peptide polyclonal antibody, raised against a sequence adjacent to the putative nuclear localization sequence, detected the IT15 protein in the nucleus of human cells. These results extend and confirm the previous localization studies and identify an IT15 peptide motif that can function for nuclear localization.
Brain Res Mol Brain Res 1995 Oct
PMID:The identification of a functional nuclear localization signal in the Huntington disease protein. 877 58


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