Abstract for presentation at 11th International Congress of Human Genetics

A Novel Pathogenic Mutation and Possible Synergistic Heterozygosity Contributing to Respiratory Chain Complex I Deficiency

  • Dr Renato Salemi, Murdoch Children's Research Institute, Royal Children’s Hospital, Melbourne, Australia
  • Dr Lisa Worgan, Department of Medical Genetics, Sydney Children’s Hospital, Australia
  • Dr Avihu Boneh, Genetic Health Services Victoria, Royal Children’s Hospital, Melbourne, Australia
  • Dr Denise Kirby, Murdoch Children’s Research Institute, Royal Children’s Hospital, Australia
  • Dr David Thorburn, Murdoch Children’s Research Institute, Royal Children’s Hospital, Australia

    • We identified three Middle-Eastern patients with Leigh syndrome, who had a novel pathogenic mutation in the NDUFS4 gene, encoding a complex I subunit. Patient A was homozygous for a frameshift mutation (c.221delC), giving rise to a crippled complex I, smaller than the wild-type complex visualized by BN-PAGE. Two affected siblings from a second family were heterozygous for c.221delC but no other coding region mutations were found by genomic and cDNA sequencing. Microsatellite markers showed the mutant allele was identical by descent in all three patients and that the heterozygous sibs had the same non-c.221delC allele. Unlike patient A and other NDUFS4 patients, the two affected sibs had normal complex I activity in fibroblasts but deficient activity in muscle. Two mechanisms were studied as possible explanations for a pathogenic role of the heterozygous c.221delC mutation:
    (1)Tissue-specific silencing of the non-c.221delC allele by a mutation in a cis- or trans-acting regulatory element. qPCR of brain and muscle showed no significant decrease in NDUFS4 mRNA compared to control. The absence of crippled complex I on BN-PAGE analysis of muscle further indicates that the defect in this family is not related solely to decreased expression of NDUFS4.
    (2)Synergistic heterozygosity, in which one mutant NDUFS4 allele may interact with a mutation in another subunit gene or assembly factor to cause complex I deficiency. Since the family was consanguineous we suspected this may be a homozygous variant and performed homozygosity mapping using Affymetrix 50k SNP chips to identify homozygous regions common to both affecteds. We are currently studying three genes encoding Complex I subunits or putative assembly factors that were located in shared homozygous regions. We propose that the NDUFS4 mutation may predispose these patients to complex I deficiency by interacting with a sequence variant elsewhere that would not normally be pathogenic if present without the NDUFS4 mutation.

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