Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A transcription map of the Huntington disease gene region was generated by a direct cDNA selection strategy using genomic DNA from the 4p16.3 region surrounding the D4S95 and D4S127 loci. A total of 58 cDNA fragments were obtained from cDNAs derived from fetal brain, frontal cortex, liver and bone marrow following hybridization to overlapping YACs from this region. These cDNA clones were aligned into transcription units by hybridization to specific mRNAs, by sequence overlap and by physical mapping onto overlapping YAC clones. Nine separate transcription units spanning approximately one megabase were detected by RNA hybridization. They represent a minimum number of genes in this region and do not include those genes expressed specifically in tissues not used for the hybridization. The transcription map that is provided by the cDNA segments will lead to the generation of a detailed gene map of this region.
Hum Mol Genet 1993 Jul
PMID:A transcription map of the region containing the Huntington disease gene. 768

Huntington's disease (HD) is an inherited neurodegenerative disorder expressed when a trinucleotide repeat in the gene IT-15 is expanded. The mechanism by which the expanded repeat causes the expression of the disease is unknown. Possible mechanisms include alterations in the amount of the mRNA, potentially resulting from changes in gene transcription or abnormal mRNA stability. In order to determine whether the expanded IT-15 allele is present in mRNA, we isolated total RNA from the cortex and striatum of patients and controls. To distinguish the two alleles of the IT-15 transcript in HD patients, we amplified across a region containing a dimorphic single triplet deletion observed on some chromosomes and found that the relative intensity of the two PCR bands amplified from genomic DNA and those amplified from first strand cDNA from brain tissue were essentially equal. In order to determine whether the exon containing the expanded CAG repeat is present in IT-15 mRNA from HD patients, we amplified across this region and demonstrated the presence of the expanded repeat in cDNA from both striatum and cortex. Based on this evidence, we suggest that the mechanism of disease expression does not occur during transcription or in the stability of the RNA, but rather occurs during translation or postranslationally.
Hum Mol Genet 1995 Jan
PMID:Expression of the mutant allele of IT-15 (the HD gene) in striatum and cortex of Huntington's disease patients. 771 29

We have analysed the CAG repeat in the Huntington disease (HD) gene in sperm and blood from 20 unrelated HD patients. Although the CAG repeat displayed significant mosaicism in sperm from all individuals, there were marked differences in the degree of repeat instability. Individuals who had either inherited or transmitted an expanded CAG repeat displayed the highest levels of repeat mosaicism, whereas individuals who had inherited or transmitted a contracted repeat had very limited CAG mosaicism in sperm. A strong association between intergenerational change in CAG allele size and the level of sperm repeat mosaicism was determined (P = 0.019). In contrast, neither blood CAG size nor repeat mosaicism in blood, were significantly associated with intergenerational CAG changes. These data suggest the presence of a cis-acting factor, separate from CAG size, that strongly influences the intergenerational behaviour of the CAG repeat. Additional studies are needed to determine whether analysis of CAG mosaicism in sperm is useful for assessing an individual's risk for transmitting large expansions or contractions to his offspring.
Hum Mol Genet 1995 Feb
PMID:Somatic mosaicism in sperm is associated with intergenerational (CAG)n changes in Huntington disease. 775 66

The discovery of the intragenic delta 2642 deletion/insertion polymorphism in the Huntington's disease (HD) gene provides a tool to explore HD evolution, as the deletion is rare in normal chromosomes but overrepresented in HD chromosomes. Thus, delta 2642 deletion alleles were thought to mark normal chromosomes that are particularly prone to becoming HD chromosomes. We have examined this polymorphism in a range of human and non-human primate populations. Our results suggest that the deletion event probably occurred in the human lineage on a chromosome with a CAG allele length at the upper end of the normal size range, as the deletion seemed to be only associated with human chromosomes with 20 or more repeats. These deletion chromosomes are prone to expansion into the HD range because they are at the upper end of the normal range. These data explain the apparent 'founder' HD haplotype defined by the deletion and suggest that chromosomes carrying the deletion are no more mutable than non-deletion chromosomes with similar sized CAG repeats.
Hum Mol Genet 1995 Feb
PMID:Haplotype analysis of the delta 2642 and (CAG)n polymorphisms in the Huntington's disease (HD) gene provides an explanation for an apparent 'founder' HD haplotype. 775 68

This study addresses genetic factors associated with normal variation of the CAG repeat in the Huntington disease (HD) gene. To achieve this, we have studied patterns of variation of three trinucleotide repeats in the HD gene including the CAG and adjacent CCG repeats as well as a GAG polymorphism at residue 2642 (delta 2642). We have previously demonstrated that variation in the CCG repeat is associated with variation of the CAG repeat length on normal chromosomes. Here we show that differences in the GAG trinucleotide polymorphism at residue 2642 is also significantly correlated with CAG size on normal chromosomes. The B allele which is associated with higher CAG repeat lengths on normal chromosomes is markedly enriched on affected chromosomes. Furthermore, this glutamic acid polymorphism shows significant variation in different ancestries and is absent in chromosomes of Japanese, Black and Chinese descent. Haplotype analysis of both the CCG and delta 2642 polymorphisms have indicated that both are independently associated with differences in CAG length on normal chromosomes. These findings lead to a model for the genetic evolution of new mutations for HD preferentially occurring on normal chromosomes with higher CAG repeat lengths and a CCG repeat length of seven and/or a deletion of the glutamic acid residue at delta 2642. This study also provides additional evidence for genetic contributions to demographic differences in prevalence rates for HD.
Hum Mol Genet 1995 Feb
PMID:Ancestral differences in the distribution of the delta 2642 glutamic acid polymorphism is associated with varying CAG repeat lengths on normal chromosomes: insights into the genetic evolution of Huntington disease. 775 69

The neurodegenerative disorder Huntington disease (HD) appears to be caused by an increase in the number of repeats of the trinucleotide CAG located near the 5' end of the gene. The nucleotide sequences of the cDNA and the gene predict that the HD protein has a molecular weight of 347,000 (3144 amino acids) and that the CAG repeats encode a segment of polyglutamine beginning 17 amino acids from the amino terminus. Because the CAG repeat plays such a critical role in the etiology of the disease, we sought to obtain evidence that the polyglutamine segment is indeed present in the protein. We used two peptides, hd1-peptide (FESLKSFQQ), predicted to lie at amino acid positions 11-19, just amino-terminal to the polyglutamine segment, and hd2-peptide (QQPRNKPLK), predicted to lie at amino acid positions 2531-2539, to induce polyclonal antibodies in NZW rabbits. Both antibodies recognize a protein on Western blots of about 350 kDa in cell lysates from human brain tissue and human and monkey cell lines, including cells from individuals heterozygous and homozygous for the disease. These results suggest that the HD protein in these cells contains the predicted amino terminal segment, and by inference, the segment of polyglutamine, and that the protein is expressed even when only mutant copies of the gene are present. Interestingly, the antibody to hd1-peptide does not recognize the HD protein on Western blots containing lysates from rodent cell lines, whereas the antibody to hd2-peptide does. This discrimination provides a useful means to assay for the presence of the human HD protein in a rodent cell background.
Hum Mol Genet 1995 Mar
PMID:Evidence from antibody studies that the CAG repeat in the Huntington disease gene is expressed in the protein. 779 4

This study of allelic association using three intra- and two extragenic markers within 150 kb of the Huntington disease (HD) mutation has provided evidence for linkage disequilibrium for four of five markers. Haplotype analysis of 67 HD families using markers in strong linkage disequilibrium with HD identified two haplotypes underlying 77.6% of HD chromosomes. Normal chromosomes with these two haplotypes had a mean number of CAG repeats significantly larger than and an altered distribution of CAG repeats compared with other normal chromosomes. Furthermore, haplotype analysis of five new mutation families reveals that HD has arisen on these same two chromosomal haplotypes. These findings suggest that HD arises more frequently on chromosomes with specific DNA haplotypes and higher CAG repeat lengths. We then studied CAG and CCG repeat lengths in the HD gene on 896 control chromosomes from different ancestries to determine whether the markedly reduced frequency of HD in Finland, Japan, China and African Blacks is associated with an altered frequency of DNA haplotypes and subsequently lower CAG lengths on control chromosomes compared to populations of Western European descent. The results show a highly significant inverse relationship between CAG and CCG repeat lengths. In populations with lowered prevalence rates of HD, CAG repeat lengths are smaller and the distribution of CCG alleles is markedly different from Western European populations. These findings suggest that, in addition to European emigration, new mutations make a contribution to geographical variation of prevalence rates and is consistent with a multistep model of HD developing from normal chromosomes with higher CAG repeat lengths.
Hum Mol Genet 1994 Dec
PMID:DNA haplotype analysis of Huntington disease reveals clues to the origins and mechanisms of CAG expansion and reasons for geographic variations of prevalence. 788 6

Previous autoradiographic studies have shown that serotonin 5-HT2 receptors are homogeneously distributed in the human striatum. While these studies were done using antagonist radioligands such as [3H]ketanserin, we describe here a heterogeneous distribution of 5-HT2 binding sites in the human striatum, using [3H]LSD and [125I]DOI as ligands. Beside their agonist properties, these compounds belong to the family of psychedelic drugs. The localization of their binding sites in the dorsal striatum is very similar to that of striosomes, as visualized by acetylcholinesterase histochemistry or [3H]flunitrazepam labelling. This heterogeneous distribution seems to be a peculiarity of the human and guinea-pig brain, for it is not found in the monkey, cat, pig, and cow. In the rat striatum, a weak patchniness was seen, but corresponded to 5-HT1C binding sites. The density of [125I]DOI binding sites over striosomes presents large variations, which can neither be correlated with parameters such as age, gender and post-mortem delay nor with the effects of neurodegenerative disorders, with the exception of Huntington's disease, at late stages of the disease. The drug binding profile of [125I]DOI binding sites in the striosomes is identical to that of matrix binding sites. It is also fully comparable to the pharmacological profile of cortical 5-HT2 sites reported using [3H]ketanserin as a radioligand, with the exception of the higher affinity displayed by agonists for [125I]DOI binding sites. Interestingly, biphasic displacement curves yield a better fit for spiperone, cinanserin and ketanserin competitions. This biphasic profile can probably neither be accounted for by the presence of 5-HT1C sites nor by the existence of multiple affinity states. Taken together, these data suggest that a heterogeneous population of 5-HT2 receptors is present on the cell bodies or dendrites of striosomal neurons. These receptors provide an additional anatomical substrate to explain the psychedelic action of indoleamine (LSD) and phenylethylamine (DOI, DOM) drugs.
Brain Res Mol Brain Res 1994 Jul
PMID:Binding sites for 5-hydroxytryptamine-2 receptor agonists are predominantly located in striosomes in the human basal ganglia. 796 58

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

Neuropeptide Y (NPY)-containing neurons are depleted in the cortices of individuals with Alzheimer disease (AD), yet spared in the striatum of patients with Huntington chorea. It is unknown whether this neuronal phenotype is inherently susceptible to the neurodegenerative processes that are a hallmark of AD. To study this question, the murine trisomy 16 model of Down syndrome and Alzheimer disease was investigated. Since trisomic fetuses die in utero, studies were carried out on primary cultures of dissociated cortical neurons. These were prepared from 15-d gestational trisomy 16 fetuses and their littermate euploid controls, and examined by immunocytochemical staining for neuropeptide Y at 7 and 12 d in vitro. Trisomy 16 neurons were also grown on euploid glial carpets, whereas euploid neurons were grown on trisomic glia. The results demonstrate a significant increase in the number of NPY neurons and a stunting in the dendritic arbor of these neurons in trisomic vs euploid cortex. Both of these parameters could be normalized by direct contact with euploid glia. When euploid cortex was plated on trisomic glia, the number of NPY neurons and their morphology were altered so that they began to resemble trisomic NPY cortical neurons. These results indicate a dysregulation of NPY neuronal expression and differentiation in trisomy 16 cortex that are modifiable by interaction with euploid glia and imply an abnormal trophic (glial) environment in trisomic cortex.
Mol Chem Neuropathol 1994 Aug
PMID:Neuropeptide Y immunoreactive neurons in murine trisomy 16 cortical cultures. Plasticity of expression and differentiation. 799 28


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>