POLG exon 22 skipping induced by different mechanisms in two unrelated cases of Alpers syndrome

Mitochondrion. 2011 Jan;11(1):223-7. doi: 10.1016/j.mito.2010.07.011. Epub 2010 Aug 4.

Abstract

The POLG genes were sequenced in two unrelated patients presenting with Alpers syndrome. The novel c.3626_3629dupGATA and the c.3643+2T>C alleles were associated in trans with p.A467T and p.[W748S;E1143G], respectively. POLG transcripts from skin fibroblasts showed complete exon 22 skipping for patient 2, but surprisingly partial exon 22 skipping from the c.3626_3629dupGATA for patient 1. The creation of a putative exonic splicing silencer could be responsible for the splicing anomaly observed in patient 1. Both c.3643+2T>C and c.3626_3629dupGATA create a premature termination codon and a low polymerase γ activity in skin fibroblasts is responsible for the severe phenotype in these patients.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Child, Preschool
  • Codon, Nonsense / genetics
  • DNA Polymerase gamma
  • DNA-Directed DNA Polymerase / genetics*
  • DNA-Directed DNA Polymerase / metabolism
  • Diffuse Cerebral Sclerosis of Schilder / diagnosis
  • Diffuse Cerebral Sclerosis of Schilder / genetics*
  • Exons / genetics*
  • Fatal Outcome
  • Female
  • Fibroblasts / metabolism
  • Genetic Variation*
  • Humans
  • Male
  • Mitochondria / enzymology
  • Mitochondria / genetics
  • Mutation
  • RNA Splicing*
  • Sequence Analysis, DNA

Substances

  • Codon, Nonsense
  • DNA Polymerase gamma
  • DNA-Directed DNA Polymerase
  • POLG protein, human