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O Mukherjee,
P Meera,
S Ghosh,
S Kubendran,
K Kiran,
K R Manjunath,
M N Subhash,
V Benegal, S K Brahmachari,
P P Majumder,
S Jain
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ABSTRACT: The genetic basis of bipolar disorder (BPD) and schizophrenia (SCZ) has been established through numerous clinical and molecular studies. Although often considered separate nosological entities, evidence now suggests that the two syndromes may share some genetic liability. Recent studies have used a composite phenotype (psychosis) that includes BPD, SCZ, psychosis not otherwise specified, and schizoaffective disorder, to identify shared susceptibility loci. Several chromosomal regions are reported to be shared between these syndromes (18p, 6q, 10p, 13q, 22q). As a part of our endeavor to scan these regions, we report a positive linkage and association finding at 18p11.2 for psychosis. Two-point linkage analysis performed on a series of 52 multiplex pedigrees with 23 polymorphic markers yielded a LOD score of 2.02 at D18S37. An independent set of 159 parent offspring trios was used to confirm this suggestive finding. The TDT analysis yielded support for association between the marker D18S453 and the disease allele (chi2 = 4.829, P < 0.028). This region has been implicated by several studies on BPD [Sjoholt et al. (2004); Mol Psychiatry 9(6):621-629; Washizuka et al. (2004); Biol Psychiatry 56(7):483-489; Pickard et al. (2005); Psychiatr Genet 15(1):37-44], SCZ [Kikuchi et al. (2003); J Med Dent Sci 50(3):225-229; Babovic-Vuksanovic et al. (2004); Am J Med Genet 124(3):318-322] and also as a shared region between the two diseases [Ishiguro et al. (2001); J Neural Transm 108(7):849-854; Reyes et al. (2002); Mol Psychiatry 7(4):337-339; Craddock et al. (2005); J Med Genet 42(3):193-204]. Our findings provide an independent validation of the above reports, and suggest the presence of susceptibility loci for psychoses in this region.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 12/2006; 141B(8):868-73. · 3.70 Impact Factor
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O. Mukherjee,
P. Meera,
S. Ghosh,
S. Kubendran,
K. Kiran,
K.R. Manjunath,
M.N. Subhash,
V. Benegal, S.K. Brahmachari,
P.P. Majumder,
S. Jain
[show abstract]
[hide abstract]
ABSTRACT: The genetic basis of bipolar disorder (BPD) and schizophrenia (SCZ) has been established through numerous clinical and molecular studies. Although often considered separate nosological entities, evidence now suggests that the two syndromes may share some genetic liability. Recent studies have used a composite phenotype (psychosis) that includes BPD, SCZ, psychosis not otherwise specified, and schizoaffective disorder, to identify shared susceptibility loci. Several chromosomal regions are reported to be shared between these syndromes (18p, 6q, 10p, 13q, 22q). As a part of our endeavor to scan these regions, we report a positive linkage and association finding at 18p11.2 for psychosis. Two-point linkage analysis performed on a series of 52 multiplex pedigrees with 23 polymorphic markers yielded a LOD score of 2.02 at D18S37. An independent set of 159 parent offspring trios was used to confirm this suggestive finding. The TDT analysis yielded support for association between the marker D18S453 and the disease allele (χ2 = 4.829, P < 0.028). This region has been implicated by several studies on BPD [Sjoholt et al. (2004); Mol Psychiatry 9(6):621–629; Washizuka et al. (2004); Biol Psychiatry 56(7):483–489; Pickard et al. (2005); Psychiatr Genet 15(1):37–44], SCZ [Kikuchi et al. (2003); J Med Dent Sci 50(3):225–229; Babovic-Vuksanovic et al. (2004); Am J Med Genet 124(3):318–322] and also as a shared region between the two diseases [Ishiguro et al. (2001); J Neural Transm 108(7):849–854; Reyes et al. (2002); Mol Psychiatry 7(4):337–339; Craddock et al. (2005); J Med Genet 42(3):193–204]. Our findings provide an independent validation of the above reports, and suggest the presence of susceptibility loci for psychoses in this region. © 2006 Wiley-Liss, Inc.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 08/2006; 141B(8):868 - 873. · 3.70 Impact Factor
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ABSTRACT: To understand the population variation and haplotypes of Huntington's disease (HD) in India we have analysed CAG repeats at the HD locus together with closely linked polymorphisms in both HD patients and normal controls.
The CAG repeat and linked polymorphisms were analysed in 30 Indian HD families together with 250 ethnically matched controls using fluorescent polymerase chain reaction (PCR) based size estimation.
CAG repeats at the HD locus in the normal population showed a mean size of 17.99 +/- 2.66 repeats (range nine to 33 repeats). The HD mutation in our families did not show any significant association with either the (CCG)7 or (CCG)10 allele while haplotype analysis suggested the over-representation of the 7-2-I (CCG-D4s127-Delta 2642 loci) haplotype in a subset of families.
The distribution of CAG repeats in the normal population suggests a higher prevalence of HD, closer to that seen in Western Europe. Haplotype analysis suggests the presence of a founder mutation in a subset of families and provides evidence for multiple and geographically distinct origins for the HD mutation in India.
Acta Neurologica Scandinavica 11/2003; 108(4):281-6. · 2.47 Impact Factor
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ABSTRACT: A better understanding of human genetic variation is important in assessing disease epidemiology and phenotypic variation, and may be critical in evaluating genetic aspects of common genetic diseases, such as schizophrenia, bipolar disease and Parkinson's. These diseases are particularly difficult to investigate as there are few peripheral markers, and although a genetic aetiology has long been suspected, robust findings have been hard to establish.
Variations in alleles at 13 tri-nucleotide gene loci expressed in the brain and implicated in several neurodegenerative diseases, as well as certain other loci, were examined in the Indian population for comparison with other major ethnic groups.
In the Indian population, the distribution of alleles at the Machado-Joseph disease locus was similar to the Western European pattern of distribution. Analysis of haplotypes at the locus for Huntington's disease suggested multiple origins, and possible effects of population admixture because of the recent history of the country. At other alleles of neuropsychiatric interest (dopamine receptor, serotonin receptor, serotonin transporter, alcohol dehydrogenase), allele frequencies in the Indian population differed from other populations. Interspecies comparison suggests a gradual expansion in repeat size, with the exception of the CLOCK gene, which displays a contraction of CAG repeat numbers. World-wide differences in disease phenotypes need to be explored, and an appreciation of their genetic basis may provide a window of opportunity for improving our knowledge of the underlying genetic mechanisms.
Community Genetics 02/2002; 5(3):171-7. · 1.32 Impact Factor
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ABSTRACT: Spinocerebellar ataxia 12 (SCA12) is a recently identified form of autosomal dominant cerebellar ataxia associated with the expansion of an unstable CAG repeat in the 5' untranslated region of the gene PPP2R2B. We analyzed 77 Indian families with autosomal dominant cerebellar ataxia phenotype and confirmed the diagnosis of SCA12 in 5 families, which included a total of 6 patients and 21 family members. The sizes of the expanded alleles ranged from 55 to 69 CAG repeats, and the sizes of the normal alleles ranged from 7 to 31 repeats. We believe our study is the first to demonstrate that SCA12 may not be as rare in some populations as previously thought.
Annals of Neurology 01/2002; 50(6):796-800. · 11.09 Impact Factor
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ABSTRACT: Chromosome 22 has been implicated in schizophrenia and bipolar disorder in a number of linkage, association and cytogenetic studies. Recent evidence has also implicated CAG repeat tract expansion in these diseases. In order to explore the involvement of CAG repeats on chromosome 22 in these diseases, we have created an integrated map of all CAG repeats > or =5 on this chromosome together with microsatellite markers associated with these diseases using the recently completed nucleotide sequence of chromosome 22. Of the 52 CAG repeat loci identified in this manner, four of the longest repeat stretches in regions previously implicated by linkage analyses were chosen for further study. Three of the four repeat containing loci, were found in the coding region with the CAG repeats coding for glutamine and were expressed in the brain. All the loci studied showed varying degrees of polymorphism with one of the loci exhibiting two alleles of 7 and 8 CAG repeats. The 8-repeat allele at this locus was significantly overrepresented in both schizophrenia and bipolar patient groups when compared to ethnically matched controls, while alleles at the other three loci did not show any such difference. The repeat lies within a gene which shows homology to an androgen receptor related apoptosis protein in rat. We have also identified other candidate genes in the vicinity of this locus. Our results suggest that the repeats within this gene or other genes in the vicinity of this locus are likely to be implicated in bipolar disorder and schizophrenia.
Molecular Psychiatry 12/2001; 6(6):694-700. · 13.67 Impact Factor
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ABSTRACT: Spinocerebellar ataxia 2 (SCA2) is an autosomal dominant neurodegenerative disorder that results from the expansion of a cryptic CAG repeat within the exon 1 of the SCA2 gene. The CAG repeat in normal individuals varies in length from 14 to 31 repeats and is frequently interrupted by one or more CAA triplets, whereas the expanded alleles contain a pure uninterrupted stretch of 34 to 59 CAG repeats. We have previously reported the presence of a limited pool of 'ancestral' or 'at risk' haplotypes for the expanded SCA2 alleles in the Indian population. We now report the identification of two novel single nucleotide polymorphisms (SNPs) in exon 1 of the SCA2 gene and their characterization in 215 normal and 64 expanded chromosomes. The two biallelic SNPs distinguished two haplotypes, GT and CC, each of which formed a predominant haplotype associated with normal and expanded SCA2 alleles. All the expanded alleles segregated with CC haplotype, which otherwise was associated with only 29.3% of the normal chromosomes. CAA interspersion analysis revealed that majority of the normal alleles with CC haplotype were either pure or lacked the most proximal 5' CAA interruption. The repeat length variation at SCA2 locus also appeared to be polar with changes occurring mostly at the 5' end of the repeat. Our results demonstrate that CAA interruptions play an important role in conferring stability to SCA2 repeat and their absence predisposes alleles towards instability and pathological expansion. Our study also provides new haplotypes associated with SCA2 that should prove useful in further understanding the mutational history and mechanism of repeat instability at the SCA2 locus.
Human Molecular Genetics 11/2001; 10(21):2437-46. · 7.64 Impact Factor
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ABSTRACT: Angiotensin converting enzyme (ACE) gene I/D polymorphism has been associated with high altitude (HA) disorders as well as physical performance. We, however, envisage that the polymorphism may be associated with adaptation to the hypobaric hypoxia of altitude, thus facilitating physical performance. For this purpose, three unrelated adult male groups, namely (1) the Ladakhis (HLs), who reside at and above a height of 3600 m, (2) lowlanders, who migrated to Ladakh (MLLs), and (3) resident lowlanders (LLs), have been investigated. The HLs had significantly (p & 0.001) greater numbers of the II homozygotes and the ID heterozygotes than the DD homozygotes, the genotype distribution being 0.46, 0.43 and 0.11 for II, ID and DD genotypes respectively. The MLLs comprised 60% II homozygotes, which was higher (p & 0.001) than the HLs (46%). In the LLs, the heterozygotes were greater (p & 0.001) in number than the II and DD homozygotes. The I allele frequency was 0.72 in the MLLs, 0.67 in the HLs and 0.55 in the LLs. Polymorphism study suggested that the II genotype could be associated with altitude adaptation, which might influence physical efficiency.
Annals of Human Genetics 11/2001; 65(Pt 6):531-6. · 2.57 Impact Factor
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ABSTRACT: The most common mutation associated with Progressive Myoclonus Epilepsy (EPM1) of Unverricht-Lundberg type is the expansion of a dodecamer repeat, d(CCCCGCCCCGCG)n. We show that the C-rich strand of this repeat (2-3 copies) forms intercalated i-motif structure at acidic pH as judged by CD spectroscopy and anomalous gel electrophoretic mobility. The stability of the structure increases with the increase in the length of the repeat. Transient formation of stable, folded back structure like i-motif could play an important role in the mechanism of expansion of this repeat.
Journal of biomolecular structure & dynamics 11/2001; 19(2):307-13. · 4.99 Impact Factor
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ABSTRACT: The secondary structure of DNA has been shown to be an important component in the mechanism of expansion of the trinucleotide repeats that are associated with many neurodegenerative disorders. Recently, expansion of a dodecamer repeat, (CCCCGCCCCGCG)n upstream of cystatin B gene has been shown to be the most common mutation associated with Progressive Myoclonus Epilepsy (EPM1) of Unverricht-Lundborg type. We have investigated structure of oligonucleotides containing one, two and three copies of the EPM1 repeat sequences at physiological pH. CD spectra and anomalous faster gel electrophoretic mobilty indicates formation of intramolecularly folded structures that are formed independent of concentration. Hydroxylamine probing allowed us to identify the C residues that are involved in C.G base pairing. P1 nuclease studies elucidated the presence of unpaired regions in the folded back structures. UV melting studies show biphasic melting curves for the oligonucleotides containing two and three EPM1 repeats. Our data suggests multiple hairpin structures for two and three repeat containing oligonucleotides. In this paper we show that oligonucleotides containing EPM1 repeat adopt secondary structures that may facilitate strand slippage thereby causing the expansion.
Journal of biomolecular structure & dynamics 11/2001; 19(2):293-305. · 4.99 Impact Factor
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ABSTRACT: Circadian rhythms play a central role in diverse physiological phenomena and the recent years have witnessed the identification of a number of genes responsible for the maintenance of these rhythms. One of these is the Clock gene, which was first identified in mouse and subsequently in a large number of organisms, including humans. The human Clock gene has been proposed as a possible candidate for disorders affected by alterations of circadian rhythm, including bipolar disorder and schizophrenia. This gene contains a highly conserved polyglutamine motif, that in humans is coded for by CAG repeats. In view of the involvement of CAG repeat expansion in a number of neuro-psychiatric disorders, we have sought to determine the polymorphism status of CAG repeats at the Clock locus in humans. Our analysis of 190 unrelated individuals, who included patients suffering from bipolar disorder and schizophrenia, indicated that the repeat, which consisted of 6 CAG triplets, was not polymorphic in humans. An analysis of the repeat in non-human primates and other organisms revealed that the glutamine stretch is shortest in humans and baboons, and longest in Drosophila and zebrafish. A study of various Drosophila species revealed that the repeat number is highly polymorphic, ranging from 25 to 33 pure glutamine repeats. Unlike most other microsatellites, the CAG repeat stretch at the Clock locus in humans is smaller than its homologues in non-human primates. We propose that glutamine repeat size is functionally important in this gene and thus tightly regulated. The variation in repeat number is probably deleterious to the individual, resulting in the maintenance of a short and invariable repeat structure in the human population.
Human Genetics 09/2001; 109(2):136-42. · 5.07 Impact Factor
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ABSTRACT: Poly purine.pyrimidine sequences have the potential to adopt intramolecular triplex structures and are overrepresented upstream of genes in eukaryotes. These sequences may regulate gene expression by modulating the interaction of transcription factors with DNA sequences upstream of genes.
A poly purine.pyrimidine sequence with the potential to adopt an intramolecular triplex DNA structure was designed. The sequence was inserted within a nucleosome positioned upstream of the beta-galactosidase gene in yeast, Saccharomyces cerevisiae, between the cycl promoter and gal 10 Upstream Activating Sequences (UASg). Upon derepression with galactose, beta-galactosidase gene expression is reduced 12-fold in cells carrying single copy poly purine.pyrimidine sequences. This reduction in expression is correlated with reduced transcription. Furthermore, we show that plasmids carrying a poly purine.pyrimidine sequence are not specifically lost from yeast cells.
We propose that a poly purine.pyrimidine sequence upstream of a gene affects transcription. Plasmids carrying this sequence are not specifically lost from cells and thus no additional effort is needed for the replication of these sequences in eukaryotic cells.
BMC Molecular Biology 02/2001; 2:11. · 2.86 Impact Factor
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Q Saleem,
V S Sreevidya,
J Sudhir,
J V Savithri,
Y Gowda,
C B-Rao,
V Benegal,
P P Majumder,
A Anand, S K Brahmachari,
S Jain
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ABSTRACT: Bipolar affective disorder and schizophrenia are severe behavioral disorders with a lifetime risk of approximately 1% in the population worldwide. There is evidence that these diseases may manifest the phenomenon of anticipation similar to that seen in diseases caused by trinucleotide repeat expansions. A recent report has implicated a potassium channel-coding gene, KCNN3, which contains a polymorphic CAG repeat in its coding region, in schizophrenia and bipolar disorder. We have tried to confirm these findings in Indian patients suffering from bipolar disorder and schizophrenia. No statistically significant evidence for the presence of an excess of longer alleles in the patient population, as compared to ethnically matched controls, was found. However, an analysis of the difference of allele sizes revealed a significantly greater number of patients with schizophrenia having differences of allele sizes > or = 5 when compared to normal controls. This finding may be of functional significance as the KCNN3 protein is thought to act as a tetramer, and a large difference in allele sizes would result in an asymmetric molecule with a different number of glutamine residues in each monomer. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:744-748, 2000.
American Journal of Medical Genetics 12/2000; 96(6):744-8.
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ABSTRACT: A variable number tandem repeat (VNTR) polymorphism consisting of multiple copies of a 17-bp repeat in the second intron of the serotonin transporter gene (SERT) has been reported. Different alleles of this VNTR have been found to be associated with bipolar disorder and schizophrenia. These findings have been confirmed in some populations, but disconfirmed in others. Furthermore, significant ethnic variations in the distribution of these alleles both in normal and patient populations also have been reported. We analyzed the VNTR polymorphism in 50 Indian patients with bipolar disorder and in ethnically matched controls. Two alleles corresponding to 10 and 12 repeats of the VNTR were found in both groups. There were no significant differences either in allele frequency or genotype frequency between the two groups. The nine-repeat allele that has been reported in Japanese and Caucasian populations was absent in our sample. Although it will be important to extend the present study in a larger sample, our initial results do not suggest any large association with alleles of the VNTR in the SERT gene and bipolar disorder in Indian patients. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:170-172, 2000.
American Journal of Medical Genetics 05/2000; 96(2):170-2.
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ABSTRACT: Expansion of CTG/CAG trinucleotide repeats has been shown to cause a number of autosomal dominant cerebellar ataxias (ADCA) such as SCA1, SCA2, SCA3/ MJD, SCA6, SCA7, SCA8 and DRPLA. There is a wide variation in the clinical phenotype and prevalence of these ataxias in different populations. An analysis of ataxias in 42 Indian families indicates that SCA2 is the most frequent amongst all the ADCAs we have studied. In the SCA2 families, together with an intergenerational increase in repeat size, a horizontal increase with the birth order of the offspring was also observed, indicating an important role for parental age in repeat instability. This was strengthened by the detection of a pair of dizygotic twins with expanded alleles showing the same repeat number. Haplotype analysis indicates the presence of a common founder chromosome for the expanded allele in the Indian population. Polymorphism of CAG repeats in 135 normal individuals at the SCA loci studied showed similarity to the Caucasian population but was significantly different from the Japanese population.
Human Genetics 03/2000; 106(2):179-87. · 5.07 Impact Factor
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ABSTRACT: The genomes of Methanococcus jannaschii, Mycoplasma genitalium, Haemophilus influenzae, Archaeoglobus fulgidus, Helicobacter pylori, Treponema pallidum, Borrelia burgdorferri, Rickettsia prowazekeii, Mycobacterium tuberculosis, Methanobacterium thermoautotrophicum, Synechocystis sp. PCC6803, Bacillus subtilis, Chlamydia trachomatis, Pyrococcus horikoshii, Aquifex aeolicus, Mycoplasma pneumoniae and Escherichia coli have been analysed for the presence of polypurine.polypyrimidine tracts, in order to understand their distribution in these genomes. We observed a variation in abundance of such sequences in these bacteria, with the archaeal genomes forming a high-abundance group and the canonical eubacteria forming a low-abundance group. The genomes of M. tuberculosis and A. aeolicus are unique among the organisms analysed here in the abnormal underrepresentation and overrepresentation of polypurine.polypyrimidine, respectively. We also observe a strand bias, i.e., a preferential occurrence of polypurines in coding strands. It varies widely among the bacteria, from the very high bias in M. jannaschii to the slightly inverse bias in the parasitic genomes of T. pallidum and C. trachomatis. The extent of strand bias, however, cannot be explained on the basis of the GC-content of the genome, use of all-purine codons or an excess in the amino acids that are encoded by such codons. The probable causes and effects of this phenomenon are discussed.
Gene 02/2000; 242(1-2):275-83. · 2.34 Impact Factor
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ABSTRACT: Expansion of CTG/CAG trinucleotide repeats has been shown to cause a number of autosomal dominant cerebellar ataxias (ADCA) such as SCA1, SCA2, SCA3/MJD, SCA6, SCA7, SCA8 and DRPLA. There is a wide variation in the clinical phenotype and prevalence of these ataxias in different populations. An analysis of ataxias in 42 Indian families indicates that SCA2 is the most frequent amongst all the ADCAs we have studied. In the SCA2 families, together with an intergenerational increase in repeat size, a horizontal increase with the birth order of the offspring was also observed, indicating an important role for parental age in repeat instability. This was strengthened by the detection of a pair of dizygotic twins with expanded alleles showing the same repeat number. Haplotype analysis indicates the presence of a common founder chromosome for the expanded allele in the Indian population. Polymorphism of CAG repeats in 135 normal individuals at the SCA loci studied showed similarity to the Caucasian population but was significantly different from the Japanese population.
Human Genetics 01/2000; 106(2):179-187. · 5.07 Impact Factor
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ABSTRACT: Expansion of triplet repeats has been seen to underlie several disorders that manifest anticipation. Clinical evidence suggests that anticipation occurs in the major psychoses. We studied the distribution of repeat sizes at the Machado-Joseph disease (MJD) locus in a group of patients with the major psychoses. We did not find any large expansions, though 2 patients had alleles that were two repeats larger than in our controls. The difference in allele sizes was larger in the patient sample as compared to the controls. The effect of such large differences might be of functional significance.
American Journal of Medical Genetics 10/1998; 81(5):440-2.
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ABSTRACT: The molecular genetic analyses (PCR and Southern hybridization) of Indian patients with myotonic dystrophy (DM) were carried out to determine the degree of repeat expansion and an attempt was made to correlate the repeat number with disease severity. A scoring system based on the salient clinical features was devised to objectively assess the disease severity. The repeat expansion was seen in 11 of 12 patients examined and showed an inverse correlation with the age of onset confirming the phenomenon of anticipation. This was further established in the two pedigrees studied, clearly demonstrating both clinical and genetic anticipation. The clinical severity score, however, did not correlate well with the repeat number. Nonetheless, such molecular genetic analyses may have immense value as a screening procedure to identify premutations as well as in prenatal diagnoses.
The Indian journal of medical research 05/1998; 107:187-96. · 1.84 Impact Factor
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ABSTRACT: Genome sequence information has generated increasing evidence for the claim that repetitive DNA sequences present within and around genes could play a important role in the regulation of gene expression. Polypurine/polypyrimidine sequences [poly(Pu/Py)] have been observed in the vicinity of promoters and within the transcribed regions of many genes. To understand whether such sequences influence the level of gene expression, we constructed several prokaryotic and eukaryotic expression vectors incorporating poly(Pu/Py) repeats both within and upstream of a reporter gene, lacZ (encoding beta-galactosidase), and studied its expression in vivo. We find that, in contrast to the situation in Escherichia coli, the presence of poly(Pu/Py) sequences within the gene does not significantly inhibit gene expression in mammalian cells. On the other hand, the presence of such sequences upstream of lacZ leads to a several-fold reduction of gene expression in mammalian cells. Similar down-regulation was observed when a structural cassette containing poly(Pu/Py) sequences upstream of lacZ was integrated into yeast chromosome V. Sequence analysis of the nine totally sequenced yeast chromosomes shows that a large number of such sequences occur upstream of ORFs. On the basis of our experimental results and DNA sequence analysis, we propose that these sequences can function as cis-acting transcriptional regulators.
Gene 05/1997; 190(1):17-26. · 2.34 Impact Factor
