The deleterious G15498A mutation in mitochondrial DNA-encoded cytochrome b may remain clinically silent in homoplasmic carriers

Eur J Hum Genet. 2004 Mar;12(3):220-4. doi: 10.1038/sj.ejhg.5201132.

Abstract

We report on a patient with severe growth retardation and IgF1 deficiency, in which a mitochondrial abnormality was suspected. An isolated mitochondrial respiratory chain complex III deficiency was found in blood lymphocytes and skin fibroblasts. Sequence analysis of the cytochrome b, which is the only mitochondrial DNA-encoded subunit of complex III, revealed a homoplasmic G15498A mutation, resulting in the substitution of a highly conserved amino acid (glycine 251 into an aspartic acid). The mutation was found to be homoplasmic in all tissues examined from the mother and her brother (lymphocytes, fibroblasts, hair roots and buccal cells). Complex III deficiency was also demonstrated in these cells. Nevertheless, the mother and the brother were asymptomatic. This mutation had been considered as a cardiomyopathy-generating mutation in a previously reported case, and its pathogenicity has been demonstrated recently in yeast. However, it seems not to fulfil the classical criteria for pathogenicity of a mitochondrial DNA mutation, especially the heteroplasmic status, and to be clinically silent, albeit present, in nonaffected relatives. We suggest that other factors are contributing to the clinical variability expression of the G15498A mtDNA mutation.

Publication types

  • Case Reports

MeSH terms

  • Amino Acid Sequence
  • Aspartic Acid / genetics*
  • Child, Preschool
  • Cytochromes b / chemistry
  • Cytochromes b / genetics*
  • DNA, Mitochondrial / genetics*
  • Electron Transport / genetics
  • Electron Transport Complex III / genetics
  • Fibroblasts / enzymology
  • Genotype
  • Glycine / genetics*
  • Humans
  • Lymphocytes / enzymology
  • Male
  • Mitochondrial Diseases / enzymology
  • Mitochondrial Diseases / genetics*
  • Mitochondrial Diseases / physiopathology*
  • Molecular Sequence Data
  • Mutation, Missense / genetics*
  • Phenotype

Substances

  • DNA, Mitochondrial
  • Aspartic Acid
  • Cytochromes b
  • Electron Transport Complex III
  • Glycine