IDENTIFICATION OF THE MUTATIONS IN THE T-PROTEIN GENE CAUSING TYPICALAND ATYPICAL NONKETOTIC HYPERGLYCINEMIA

We have investigated the molecular lesions of T-protein deficiency cau sing typical or atypical nonketotic hyperglycinemia (NKH) in two unrel ated pedigrees. A patient with typical NKH was identified as being hom ozygous for a missense mutation in the T-protein gene, a Gto-A transit ion leading to a Gly-to-Asp substitution at amino acid 269 (G269D). Si bling patients of a second family with atypical NKH had two different missense mutations in the T-protein gene (compound heterozygote), a G- to-A transition leading to a Gly-to-Arg substitution at amino acid 47 (G47R) in one allele, and a G-to-A transition leading to an Arg-to-His substitution at amino acid 320 (R320H) in the other allele. Gly 269 i s conserved in T-proteins of various species, even in E. coli, whereas Gly 47 and Arg 320 are replaced by Ala and Leu, respectively, in E. c oli. The mutation occurring in more conservative amino acid residues t hus results in more deleterious damage to the T-protein, and gives the severe clinical phenotype, viz., typical NKH.