Occurrence of a 2-bp (AT) deletion allele and a nonsense (G-to-T) mutant allele at the E2 (DBT) locus of six patients with maple syrup urine disease: Multiple-exon skipping as a secondary effect of the mutations

Charles W. Fisher, Carolyn R. Fisher, Jacinta L. Chuang, Kim S. Lau, David T. Chuang, Rody P. Cox

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

We have identified two novel mutant alleles in the transacylase (E2) gene of the human branched-chain α-keto acid dehydrogenase (BCKAD) complex in 6 of 38 patients with maple syrup urine disease (MSUD). One mutation, a 2-bp (AT) deletion in exon 2 of the E2 gene, causes a frameshift downstream of residue (-26) in the mitochondrial targeting presequence. The second mutation, a G-to-T transversion in exon 6 of the E2 gene, produces a premature stop codon at Glu-163 (E163*). Transfection of constructs harboring the E163* mutation into an E2-deficient MSUD cell line produced a truncated E2 subunit. However, this mutant E2 chain is unable to assemble into a 24-mer cubic structure and is degraded in the cell. The 2-bp (AT) deletion and the E163* mutant alleles occur in either the homozygous or compound-heterozygous state in the 6 of 38 unrelated MSUD patients studied. Moreover, an array of precise single- and multiple-exon deletions were observed in many amplified E2 mutant cDNAs. The latter results appear to represent secondary effects on RNA processing that are associated with the MSUD mutations at the E2 locus.

Original languageEnglish (US)
Pages (from-to)414-424
Number of pages11
JournalAmerican Journal of Human Genetics
Volume52
Issue number2
StatePublished - 1993

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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