title: Investigation of mitochondrial DNA variations among Indian Friedreich's ataxia (FRDA) patients.
abstract: OBJECTIVE
  The loss of function mutations (biallelic) in frataxin (FXN) has primarily been implicated in Friedreich's ataxia (FRDA), an autosomal recessive cerebellar ataxia. The protein product of FXN is a nuclear-encoded mitochondrial protein required for the biogenesis of iron- clusters (Fe-S). FRDA is characterized by neurological and non-neurological features which show variable expression in affected individuals. An inverse relationship has been demonstrated between GAA repeat size and age at onset and explains 50% variability of the age at onset. MtDNA variations and haplogroups could be one of the contributory factors to explain the remaining heterogeneity in FRDA, since mitochondrial oxidative stress is thought to be involved in the pathogenesis of FRDA.
  
  
  METHODS
  In our study, targeted resequencing of the D-loop and coding region of mitochondrial genes (ND1-6 and ATP) was conducted in 30 genetically confirmed FRDA patients and 62 ethnicity-matched unrelated healthy controls to identify the functionally important mtDNA variations and to trace the mitochondrial lineage of Indian FRDA patients. Cumulative mitochondrial SNP scores were computed for the identified variations in the functional region and haplogroups were determined by Haplogrep.
  
  
  RESULTS
  A significantly higher load of overall mitochondrial variations (with a trend toward the coding region) per individual was noted among FRDA cases rather than controls (p-value<0.03). A non-synonymous variation (p. L237M) in ND2 was over-represented among FRDA cases (p-value 0.04). This variation has a reported association with longevity and myocardial infarction. We also observed over-representation of H haplogroup (Caucasian mitochondrial haplogroup) among FRDA patients. We have not observed the influence of mitochondrial variations and haplogroup upon age at onset of FRDA.
  
  
  CONCLUSIONS
  Overall, our study identifies the functionally important variations and mitochondrial lineage of Indian FRDA cases and, that underscores the importance of studying the role of mitochondrial genome variations in FRDA.
authors: Department of Neurology, Neuroscience Centre, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India.
authors: Inder
authors: I
authors: Singh
authors: Genomics and Molecular Medicine, CSIR-Institute of Genomics and Integrative Biology, Mall Road, New Delhi 110007, India. Electronic address: faruq.mohd@igib.res.in.
authors: Mohammed
authors: M
authors: Faruq
authors: Department of Neurology, Neuroscience Centre, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India.
authors: Madakasira Vasantha
authors: MV
authors: Padma
authors: Department of Neurology, Neuroscience Centre, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India.
authors: Vinay
authors: V
authors: Goyal
authors: Department of Neurology, Neuroscience Centre, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India.
authors: Madhuri
authors: M
authors: Behari
authors: Indian Council of Medical Research, Ansari Nagar, New Delhi 110029, India.
authors: Ashoo
authors: A
authors: Grover
authors: Genomics and Molecular Medicine, CSIR-Institute of Genomics and Integrative Biology, Mall Road, New Delhi 110007, India.
authors: Mitali
authors: M
authors: Mukerji
authors: Department of Neurology, Neuroscience Centre, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India. Electronic address: achalsrivastava@hotmail.com.
authors: Achal K
authors: AK
authors: Srivastava
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D005621:Friedreich Ataxia / Q000235:genetics*; D050259:Genes, Mitochondrial; D005838:Genotype; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
chemical_list: D004272:DNA, Mitochondrial
keywords: FRDA; Friedreich's ataxia; Haplogroup; Mitochondria