Genetic complementation analysis of 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency in cultured fibroblasts

O. Sovik, L. Sweetman, K. M. Gibson, W. L. Nyhan

Research output: Contribution to journalArticlepeer-review

Abstract

3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) lyase deficiency is an inherited metabolic disorder of leucine catabolism showing variability in clinical expression. We have examined the possibility of a biochemical and genetic basis for this heterogeneity by measuring the residual enzyme activities in fibroblast cultured from seven patients. The mean activity of HMG-CoA lyase was 1.1% ± 0.3% of normal with no significant differences between the patients. Genetic complementation was studied in heterokaryons obtained by fusion with polyethylene glycol using the incorporation of 1-[14C]isovaleric acid into trichloroacetic acid precipitable material to determine the activity of the leucine catabolic pathway. Unfused cells from the patients with a deficiency of HMG-CoA lyase had incorporations of less than 5% of normal. Unfused cells from patients with isovaleric acidemia or a deficiency of 3-methylcrotonyl-CoA carboxylase also had incorporations of less than 5% of normal, when fused with cells of patients with a deficiency of HMG-CoA lyase, gave positive complementation with an incorporation of 30% of normal. None of the fusions between the seven different lines deficient in HMG-CoA lyase resulted in increased incorporation. Thus, no evidence was obtained for biochemical or genetic heterogeneity in fibroblasts of these seven patients with a deficiency of HMG-CoA lyase that would account for their different clinical presentations.

Original languageEnglish (US)
Pages (from-to)791-801
Number of pages11
JournalAmerican Journal of Human Genetics
Volume36
Issue number4
StatePublished - 1984
Externally publishedYes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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