ABSTRACT
AIM: Mitochondrial DNA (mtDNA) sequence variations are associated with a number of human diseases. The 9-bp repeat sequence, CCCCCTCTA, in the intergenic region of MTCO2 and MTTK genes of the mtDNA has been extensively used in phylogenic studies. The sequence has been reported to be polymorphic in south-east Asians in isolated cases of mt diseases. This is the first systemic study identifying the role of insertion-deletion polymorphism in human disease. RESULTS: A total of 241 patients including those with cardiomyopathy, ataxias, and idiopathic neurological disorders along with 100 controls were screened; 2.9% of patients showed a single repeat (deletion) and 4.14% had three repeats (insertion), whereas all the controls had two repeats (normal). CONCLUSION: This indicates that the 9-bp insertion-deletion repeat polymorphism plays a role in disease pathology, affecting the expression of the downstream genes of mtDNA and altering ATP generation.
Subject(s)
Cardiomyopathy, Dilated/genetics , DNA, Mitochondrial/genetics , Genetic Predisposition to Disease , Nervous System Diseases/genetics , Polymorphism, Genetic/genetics , Spinocerebellar Ataxias/genetics , Case-Control Studies , Electron Transport Complex IV/genetics , Humans , Mitochondria/genetics , Mitochondria/pathology , Mutagenesis, Insertional , RNA, Transfer, Lys/genetics , Repetitive Sequences, Nucleic Acid , Sequence DeletionABSTRACT
Spinocerebellar ataxias (SCAs) are caused by expansion of (CAG)n triplet repeats. These repeats occur as polymorphic forms in general population; however, beyond a threshold size they become pathogenic. The sizes and distributions of repeats at the SCA1, SCA2, SCA3, SCA7 and DRPLA loci were assessed by molecular analysis of 124 unrelated ataxia patients and 44 controls, and the association of larger normal (LN) alleles with disease prevalence was evaluated. Triplet repeat expansions in the disease range were detected in 8% (10/124) of the cases, with the majority having expansion at the SCA1 locus. Normal allele ranges in the cohort studied were similar to the Caucasian and North Indian populations but differed from the Korean and Japanese populations at various loci. The percentage of individuals with LN alleles at the SCA1 and SCA2 loci was higher than reported in Indians, Japanese and Caucasians. LN alleles showed a good correlation with the incidence of SCA1, indicating that SCA1 is the most prevalent ataxia in our population. The majority of cases with clinical symptoms of SCA could not be diagnosed by established CAG repeat criteria, suggesting that there may be an alternative basis for disease pathogenesis: (i) Repeats lower than the normal range may also result in abnormal phenotypes (ii) LN alleles at different loci in the same individual may contribute to symptoms (iii) Exogenous factors may play a role in triggering disease symptoms in individuals with LN alleles (iv) Triplet repeats may reach the disease range in the brain but not in the blood.
Subject(s)
Spinocerebellar Ataxias/genetics , Trinucleotide Repeats/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Child , Child, Preschool , Female , Gene Frequency , Humans , India/epidemiology , Male , Middle Aged , Spinocerebellar Ataxias/epidemiology , Trinucleotide Repeat Expansion/geneticsABSTRACT
The pathological expansion of unstable trinucleotide repeats is known to cause neurodegenerative diseases. Trinucleotide repeat expansions might prove to be pathological through a variety of mechanisms, including alteration of DNA structure, transcription, RNA-protein interaction, and altered protein conformations/interactions. Deamidation of human proteins have been shown to regulate some time-dependent biological processes such as development and aging. In this paper we hypothesize the possible role of glutamine deamidation as a signaling event in the pathogenesis of neurodegenerative diseases associated with triplet repeat expansion.
