3-Hydroxy-3-methylglutaryl coenzyme A lyase (HL). Cloning of human and chicken liver HL cDNAs and characterization of a mutation causing human HL deficiency.

3-Hydroxy-3-methylglutaryl coenzyme A lyase (HL) catalyzes the final step of ketogenesis, an important pathway of mammalian energy metabolism. HL deficiency is an autosomal recessive inborn error in man leading to episodes of hypoglycemia and coma. Using the N-terminal peptide sequence of purified chicken liver HL, we designed degenerate sequence primers and amplified an 89-base pair (bp) chicken liver HL cDNA fragment. Longer cDNA clones for chicken (1384 bp) and human (1575 bp) HL were obtained by library screening. The peptide sequence predicted from the chicken clone contains two peptides from purified chicken HL. Mature human and chicken HL are 298-residue peptides. The sequence of the human clone predicts a 27-residue mitochondrial leader and a 31.6-kDa mature HL peptide. Human fibroblast and liver RNA contain a single 1.7-kilobase HL message. Two Acadian French-Canadian siblings with HL deficiency were homozygous for a 2-base pair deletion within the Ser-69 codon (S69fs(-2)), predicted to result in a truncated nonfunctional HL peptide lacking a complete active site. S69fs(-2) was not present in 12 other HL-deficient patients of 10 other ethnic origins, showing that HL deficiency is genetically heterogeneous.