Mutations and polymorphisms of the gene encoding the β-subunit of the electron transfer flavoprotein in three patients with glutaric acidemia type II

Irma Colombo, Gaetano Finocchiaro, Barbara Garavaglia, Nicoletta Garbuglio, S. Yamaguchi, F. E. Frerman, Bruno Berra, Stefano DiDonato

Research output: Contribution to journalArticlepeer-review

Abstract

Electron transfer flavoprotein (ETF) is a heterodimeric enzyme composed of an α-subunit and a β-subunit and contains a single equivalent of FAD per dimer. ETF deficiency can be demonstrated in individuals affected by a severe metabolic disorder, glutaric acidemia type II (GAII). In this study, we have investigated for the first time the molecular basis of β-ETF deficiency in three GAII patients: two Japanese brothers, P411 and P412, and a third unrelated patient, P485. Molecular analysis of the β-ETF gene in P411 and P412 demonstrated that both these patients are compound heterozygotes. One allele is carrying a G to A transition at nucleotide 518, causing a missense mutation at codon 164. This point mutation is maternally derived and is not detected in 42 unrelated controls. The other allele carries a G to C transversion at the first nucleotide of the intron donor site, downstream of an exon that is skipped during the splicing event. The sequence analysis of the β-ETF coding sequence in P485 showed only a C to T transition at nucleotide 488 that causes a Thr 154 to Met substitution and the elimination of a Hgal restriction site. Hgal restriction analysis on 63 unrelated controls genomic DNA demonstrated that the C488T transition identifies a polymorphic site. Finally, transfection of wild-type β-ETF cDNA into P411 fibroblasts suggests that wild-type β-ETF cDNA complements the genetic defect and restores the β-oxidation flux to normal levels.

Original languageEnglish
Pages (from-to)429-435
Number of pages7
JournalHuman Molecular Genetics
Volume3
Issue number3
Publication statusPublished - Mar 1994

ASJC Scopus subject areas

  • Genetics
  • Statistics, Probability and Uncertainty
  • Applied Mathematics
  • Public Health, Environmental and Occupational Health
  • Molecular Biology
  • Genetics(clinical)

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