Molecular abnormality of an inactive aldehyde dehydrogenase variant commonly found in Orientals.

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Abstract
Usual human livers contain 2 major aldehyde dehydrogenase [(ALDH) aldehyde:NAD+ oxidoreductase] isozymes.sbd.i.e., a cytosolic ALDH1 component and a mitochondrial ALDH2 component.sbd.whereas .apprxeq. 50% of Orientals are atypical and have only the ALDH1 isozyme and are missing the ALDH2 isozyme. Atypical livers contain an enzymatically inactive but immunologically crossreactive material (CRM) corresponding to the ALDH2 component. The enzymatically active ALDH2 obtained from a usual liver and the CRM obtained from an atypical liver were reduced, S-carboxymethylated, and digested by trypsin. Separation of their digests by high-performance reverse-phase chromatography and by 2-dimensional paper chromatography and electrophoresis revealed that ALDH2 contained a peptide sequence of -Glu-Leu-Gly-Glu-Ala-Gly-Leu-Gln-Ala-Asn-Val-Gln-Val-Lys- and that the Gln adjacent to Lys was substituted by Lys in CRM. All other tryptic peptides, including 8 peptides containing S-carboxymethylcysteine, were common in ALDH2 and CRM. A point mutation in the human ALDH2 locus produced the Gln .fwdarw. Lys substitution and enzyme inactivation.