title: Genetic Variation of MT-ND Genes in Frontotemporal Lobar Degeneration: Biochemical Phenotype-Genotype Correlation.
abstract: BACKGROUND
  Frontotemporal lobar degeneration (FTLD) is the second most common early-onset dementia. Over the last few decades, a growing number of evidence suggests mitochondrial involvement in neurodegeneration, namely modifications of mitochondrial DNA (mtDNA) contributing to energy impairment.
  
  
  OBJECTIVE
  To sequence the 7 mitochondrially encoded complex I (MT-ND) genes in 70 FTLD patients and investigate mitochondrial respiratory chain (MRC) complex I activity.
  
  
  METHODS
  A sample of 70 patients was studied (39 females and 31 males; age range: 38-82 years, mean ± SD: 63 ± 11 years) with a probable diagnosis of FTLD. Total DNA was extracted from peripheral blood, and sequencing analysis of 7 MT-NDn (1, 2, 3, 4L, 4, 5, 6) genes was performed. Variants identified were submitted to in silico study. Spectrophotometric evaluation of MRC activity in lymphocytes was performed, and results were compared with age-matched controls.
  
  
  RESULTS
  A total of 358 (161 different) alterations were found in 92.9% of patients. According to in silico analysis of nonsynonymous variants, only 5 variations are possibly or probably damaging. Complex I activity is significantly decreased in patients.
  
  
  CONCLUSIONS
  To our knowledge, this is the first report of the complete sequence of the MT-ND genes in FTLD patients and correlation with MRC activity. The high number of mtDNA variations identified and a significant decrease in complex I activity suggest a possible involvement of mtDNA alterations in FTLD. Although the majority of these alterations are not primarily pathogenic, an interaction with other mutations may occur, leading to the disease, worsening its expression or influencing age of onset.
authors: CNC - Center for Neuroscience and Cell Biology, Laboratory of Biochemical Genetics, University of Coimbra, Coimbra, Portugal.
authors: Rita
authors: R
authors: Gaspar
authors: Isabel
authors: I
authors: Santana
authors: Cândida
authors: C
authors: Mendes
authors: Ana Sofia
authors: AS
authors: Fernandes
authors: Diana
authors: D
authors: Duro
authors: Marta
authors: M
authors: Simões
authors: Daniela
authors: D
authors: Luís
authors: Maria João
authors: MJ
authors: Santos
authors: Manuela
authors: M
authors: Grazina
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics* / Q000503:physiopathology*; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D008297:Male; D008609:Mental Status Schedule; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009245:NADH Dehydrogenase / Q000235:genetics*; D010641:Phenotype; D013223:Statistics as Topic
chemical_list: D009245:NADH Dehydrogenase; C515075:NADH dehydrogenase subunit 1, human