title: ND4L gene concurrent 10609T>C and 10663T>C mutations are associated with Leber's hereditary optic neuropathy in a large pedigree from Kuwait.
abstract: BACKGROUND
  Leber's hereditary optic neuropathy (LHON) is a condition characterised by a rapid bilateral central vision loss due to death of the retinal ganglion cells, leading to visual impairment commonly occurring during young adulthood. The disease manifests itself more in male patients than female patients. The mtDNA mutations m.11778G>A, m.3460G>A and m.14484T>C are by far more frequent in LHON than any other mutation. In this report, a multi-generational Arab family from Kuwait with 14 male members with LHON was investigated.
  
  
  METHODS
  Complete mtDNA mutational analysis by direct Sanger's sequencing was carried out to detect pathogenic mutations, polymorphisms and haplogrouping.
  
  
  RESULTS
  All maternally related subjects from this study who were examined expressed the L3 haplotype background, with two concurrent mtDNA mutations, 10609T>C and 10663T>C, that led to non-conservative amino acid changes of Ile47Thr and Val65Ala, respectively. The two variations were absent in 144 normal and ethnicity-matched controls.
  
  
  CONCLUSIONS
  The two identified mutations associated with LHON in this family may exert their pathogenicity through a cumulative or haplogroup effect. This is the first report of the presence of two concurrent mutations in the ND4L gene in individuals with LHON who carry the L3 haplogroup.
authors.affiliation: Dasman Institute, Dasman, Kuwait.
authors.forename: Raed
authors.initials: R
authors.lastname: Behbehani
authors.affiliation: Dasman Genome Centre, Dasman Institute, Dasman, Kuwait.
authors.forename: Motasem
authors.initials: M
authors.lastname: Melhem
authors.affiliation: Dasman Genome Centre, Dasman Institute, Dasman, Kuwait.
authors.forename: Ghazi
authors.initials: G
authors.lastname: Alghanim
authors.affiliation: Senior Managements, Dasman Institute, Dasman, Kuwait.
authors.forename: Kazem
authors.initials: K
authors.lastname: Behbehani
authors.affiliation: Dasman Genome Centre, Dasman Institute, Dasman, Kuwait.
authors.forename: Osama
authors.initials: O
authors.lastname: Alsmadi
mesh_terms: D000293:Adolescent; D018912:Arabs / Q000235:genetics; D002648:Child; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D007730:Kuwait; D008297:Male; D009245:NADH Dehydrogenase / Q000235:genetics*; D029242:Optic Atrophy, Hereditary, Leber / Q000175:diagnosis / Q000235:genetics*; D010375:Pedigree; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D041623:Tomography, Optical Coherence; D014792:Visual Acuity / Q000502:physiology; D014794:Visual Fields / Q000502:physiology; D055815:Young Adult
chemical_list: D004272:DNA, Mitochondrial; C098483:NADH dehydrogenase subunit 4; D009245:NADH Dehydrogenase
keywords: Kuwait; LHON; ND4L; Pedigree; mutation