title: Analysis of mitochondrial DNA sequences in childhood encephalomyopathies reveals new disease-associated variants.
abstract: BACKGROUND
  Mitochondrial encephalomyopathies are a heterogeneous group of clinical disorders generally caused due to mutations in either mitochondrial DNA (mtDNA) or nuclear genes encoding oxidative phosphorylation (OXPHOS). We analyzed the mtDNA sequences from a group of 23 pediatric patients with clinical and morphological features of mitochondrial encephalopathies and tried to establish a relationship of identified variants with the disease.
  
  
  RESULTS
  Complete mitochondrial genomes were amplified by PCR and sequenced by automated DNA sequencing. Sequencing data was analyzed by SeqScape software and also confirmed by BLASTn program. Nucleotide sequences were compared with the revised Cambridge reference sequence (CRS) and sequences present in mitochondrial databases. The data obtained shows that a number of known and novel mtDNA variants were associated with the disease. Most of the non-synonymous variants were heteroplasmic (A4136G, A9194G and T11916A) suggesting their possibility of being pathogenic in nature. Some of the missense variants although homoplasmic were showing changes in highly conserved amino acids (T3394C, T3866C, and G9804A) and were previously identified with diseased conditions. Similarly, two other variants found in tRNA genes (G5783A and C8309T) could alter the secondary structure of Cys-tRNA and Lys-tRNA. Most of the variants occurred in single cases; however, a few occurred in more than one case (e.g. G5783A and A10149T).
  
  
  CONCLUSIONS
  The mtDNA variants identified in this study could be the possible cause of mitochondrial encephalomyopathies with childhood onset in the patient group. Our study further strengthens the pathogenic score of known variants previously reported as provisionally pathogenic in mitochondrial diseases. The novel variants found in the present study can be potential candidates for further investigations to establish the relationship between their incidence and role in expressing the disease phenotype. This study will be useful in genetic diagnosis and counseling of mitochondrial diseases in India as well as worldwide.
authors: National Centre for Cell Science, Pune, India.
authors: Aijaz A
authors: AA
authors: Wani
authors: Sajad H
authors: SH
authors: Ahanger
authors: Sharmila A
authors: SA
authors: Bapat
authors: Ashraf Y
authors: AY
authors: Rangrez
authors: Nitin
authors: N
authors: Hingankar
authors: C G
authors: CG
authors: Suresh
authors: Shama
authors: S
authors: Barnabas
authors: Milind S
authors: MS
authors: Patole
authors: Yogesh S
authors: YS
authors: Shouche
mesh_terms: D000328:Adult; D001483:Base Sequence; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D019295:Computational Biology; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000235:genetics; D005260:Female; D006801:Humans; D007223:Infant; D007888:Leigh Disease / Q000235:genetics / Q000473:pathology; D017241:MELAS Syndrome / Q000235:genetics / Q000473:pathology; D008297:Male; D017237:Mitochondrial Encephalomyopathies / Q000235:genetics* / Q000473:pathology; D008969:Molecular Sequence Data; D009154:Mutation; D009886:Ophthalmoplegia / Q000235:genetics / Q000473:pathology; D010085:Oxidative Phosphorylation; D016133:Polymerase Chain Reaction; D012346:RNA, Transfer, Amino Acyl / Q000235:genetics; D012689:Sequence Homology, Nucleic Acid
chemical_list: D004272:DNA, Mitochondrial; D012346:RNA, Transfer, Amino Acyl; D003576:Electron Transport Complex IV