Trinucleotide repeats and haplotypes at the Huntingtin locus in an Indian sample overlaps with European haplogroup A

Abstract

Huntington's disease (HD), an autosomal dominant neurodegenerative syndrome, has a world-wide distribution. An estimated 2.5-10/100,000 people of European ancestry are affected with HD, while the Asian populations have lower prevalence (0.6-3.8/100,000). The epidemiology of HD is not well described in India, and the distribution of the pathogenic CAG expansion, and the associated haplotype, in this population needs to be better understood. This study demonstrates a distribution of CAG repeats, at the HTT locus, comparable to the European population in both normal and HD affected chromosomes. Further, we provide an evidence for similarity of the HD halpotype in Indian sample to the European HD haplogroup. Funding StatementThis study is supported by Indian Council of Medical Research (ICMR/002/208/2012/00126). The sponsor of this study had no role in study design, data collection, analysis, interpretation, or writing of the report. No private corporations or other agency paid to write this article. All the authors had full access to all the data in the study. All authors have seen and given their approval for submission of the manuscript. All the authors declare no conflict of interest in study undertaken. IntroductionThe diagnosis of Huntington's disease (HD) is based on estimation of the CAG repeat length at the HTT locus 1 . The normal HTT gene contains less than 27 CAG repeats 2 , 3 , and a few normal individuals have intermediate CAG (27)(28)(29)(30)(31)(32)(33)(34)(35) repeat expansion 2 and display no symptoms suggestive of HD. Subjects with borderline CAG (36)(37)(38)(39) repeats may or may not develop symptoms. Individuals affected with HD typically have at least one HTT allele containing CAG repeat size of 40 or greater 2 , 4 .The age at onset (AAO) is inversely correlated with length of the pathogenic CAG stretch in the HTT gene 5 . Almost 50-70% of the variation observed is determined by the CAG repeat length, the remaining maybe explained by the additional influence of other cis and trans elements, as well as environmental factors 5 . Highly expanded CAG sequences cause disease onset at a younger age 6 . The fundamental mechanisms of CAG repeat instability are poorly understood.The prevalence of HD varies among different populations, with prevalence rates of 2.5 -10 per 100,000 in people of European ancestry, while the Japanese (0.11-0.45 per 100,000), Chinese ( 0.5-1 per 100,000) and African populations (<0.01 per 100, 000) show significantly lower prevalence 7 . Indian and other South Asian populations are expected to have intermediate prevalence of HD. Prevalence studies of Indian immigrants in UK, predominantly from the northern regions of the Indian subcontinent 8 suggest that HD occurs in 1.75 per 100,000 individuals. It is generally accepted from clinical experience, and family studies of different geographical regions, that HD is distributed widely in India 9 , 10 , 11 , 12 . The origin of the pathogenic CAG expansion in India is not well understood. Multiple founder effects, and admix...

Psychiatric morbidity and poor follow-up underlie suboptimal functional and survival outcomes in Huntington's disease

“…A conservative estimate of about 75,000 HD patients in India (10,14) would indicate almost a million at risk. As about a quarter of the patients eligible for the study could not be contacted, this data possibly under-represents the overall morbidity and mortality.…”

“…An increase in the number of HD cases is being noted lately, with wider availability of genetic diagnostics. It is quite likely that the prevalence rate will be similar to that in European populations with similar haplotype (14) (approximately 3-5/1,00,000 population; or about 40,000-70,000 individuals with HD in India).…”

Reactive Neuroblastosis in Huntington’s Disease: A Putative Therapeutic Target for Striatal Regeneration in the Adult Brain

“…Historically, symptoms of chorea had been observed by many physicians (Lanska, 2010 ), while George Huntington portrayed the clinical symptoms and provided the evidence for the hereditary nature of HD in 1872 (Huntington, 1872 ; Lanska, 2000 ). Since then, an enormous scientific progress has been made in understanding the biochemical, molecular genetics and pathological basis of HD worldwide (Wexler et al, 2004 ; Bates, 2005 ; Moily et al, 2014 ). In 1983, the HD Collaborative Research Group, under the direction of Nancy Wexler, successfully mapped the defective gene responsible for HD to chromosome 4p16.3 (Gusella et al, 1983 ).…”

“…However, several lines of experimental evidence of gene knockout paradigms suggested that the expression of WT HD gene is indispensable for embryogenesis, vesicular trafficking, synaptic plasticity and neuroprotection (Duyao et al, 1995 ; Dragatsis et al, 2000 ; Reiner et al, 2003 ). The unstable CAG repeat expansion of more than 35–39 in the HD gene is translated into polyglutamine (polyQ) stretches in the huntingtin protein (Bates, 2003 ; Cornett et al, 2005 ; Moily et al, 2014 ). The abnormal polyQ repeat sequence is known to cause misfolding and aggregation of the huntingtin protein (DiFiglia et al, 1997 ; Bates, 2005 ; Poirier et al, 2005 ) leading to the selective degeneration of medium spiny neurons (MSNs) in the striatum and onset of the disease (Graveland et al, 1985 ).…”

Protective Effect of Antioxidants on Neuronal Dysfunction and Plasticity in Huntington’s Disease

“…The rate of incidence of HD is considerably higher in the Caucasian population than the Asian population. While an estimate shows the prevalence and increasing trend of HD in Western Europe, Australia, North America, and the United Kingdom, India represents a large number of total HD cases in Asia [ 11 , 12 ]. Single nucleotide polymorphism (SNP) at the HTT locus in association with the genetic diversity, lifestyle, food, and environmental factors is presumed to be the reasons for the variations in the frequency of HD among the human population [ 13 ].…”