The molecular basis of pyruvate carboxylase deficiency: mosaicism correlates with prolonged survival

Mol Genet Metab. 2008 Sep-Oct;95(1-2):31-8. doi: 10.1016/j.ymgme.2008.06.006. Epub 2008 Aug 3.

Abstract

Pyruvate carboxylase (PC) deficiency (OMIM, 266150) is a rare autosomal recessive disease. The revised PC gene structure described in this report consists of 20 coding exons and four non-coding exons at the 5'-untranslated region (5'-UTR). The gene codes for three transcripts due to alternative splicing: variant 1 (NM_000920.3), variant 2 (NM_022172.2) and variant 3 (BC011617.2). PC deficiency is manifested by three clinical phenotypes-an infantile form (Type A), a neonatal form (Type B), and a benign form (Type C). We report the molecular basis for eight cases (one Type A, five Type B and two Type C) of PC deficiency. Eight novel complex mutations were identified representing different combinations of missense mutations, deletions, a splice site substitution and a nonsense mutation. The classical phenotypes (A, B and C) correlated poorly with clinical outcomes. Mosaicism was found in five cases (one Type A, three Type B and one Type C) and four of these cases had prolonged survival. Death in the fifth case resulted from unrelated medical complications. The discrepancy between the current findings and the existing classification system should be addressed to accommodate these new observations.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Alternative Splicing
  • Cells, Cultured
  • Child
  • Child, Preschool
  • Exons
  • Female
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Mosaicism*
  • Mutation
  • Polymorphism, Restriction Fragment Length
  • Pyruvate Carboxylase / genetics*
  • Pyruvate Carboxylase / metabolism
  • Pyruvate Carboxylase Deficiency Disease / enzymology
  • Pyruvate Carboxylase Deficiency Disease / genetics*
  • Pyruvate Carboxylase Deficiency Disease / mortality
  • Survival*

Substances

  • Pyruvate Carboxylase