HMG COA LYASE DEFICIENCY - IDENTIFICATION OF 5 CAUSAL POINT MUTATIONSIN CODON-41 AND CODON-42, INCLUDING A FREQUENT SAUDI-ARABIAN MUTATION, R41Q

The hereditary deficiency of 3-hydroxy-3-methylglutaryl (HMG) CoA lyas e (HL; OMIM 246450 [http:// www3.ncbi.nlm.nih.gov:80/htbin-post/Omim/d isp mim?246450]) results in episodes of hypoketotic hypoglycemia and c oma and is reported to be frequent and clinically severe in Saudi Arab ia. We found genetic diversity among nine Saudi HL-deficient probands: six were homozygous for the missense mutation R41Q, and two were homo zygous for the frameshift mutation F305fs(-2). In 32 non-Saudi HL-defi cient probands, we found three R41Q alleles and also discovered four o ther deleterious point mutations in codons 41 and 42: R41X, D42E, D42G , and D42H. In purified mutant recombinant HL, all four missense mutat ions in codons 41 and 42 cause a marked decrease in HL activity. We de veloped a screening procedure for HL missense mutations that yields re sidual activity at levels comparable to those obtained using purified HL peptides. Codons 41 and 42 are important for normal HL catalysis an d account for a disproportionate 21 (26%) of 82 of mutant alleles in o ur group of HL-deficient probands.