A MISSENSE MUTATION (HIS42ARG) IN THE T-PROTEIN GENE FROM A LARGE ISRAELI-ARAB KINDRED WITH NONKETOTIC HYPERGLYCINEMIA

Nonketotic hyperglycinemia (NKH) is caused by a mutation in the genes encoding the components of the glycine cleavage multi-enzyme system. M ore than 80% of the patients have defects in the gene encoding P-prote in, whereas the rest of the patients have defects in the gene encoding T-protein. We have found a large Israeli-Arab kindred with NKH. At le ast 14 children were affected, and all the patients had seizures and r espiratory failure within 2 days after birth. Enzymatic analysis revea led that T-protein activity was deficient in the liver specimen from o ne propositus. We screened this family for a mutation in the protein-c oding region and exon/intron boundaries of T-protein gene by direct se quencing analysis. A missense mutation was found in exon 2; this resul ted in an amino acid substitution from histidine to arginine at positi on 42 (H42R). Histidine 42 is conserved in human, bovine, chicken, pea , and Escherichia coli, suggesting that it has an important role in ca talytic functions. Genotype analyses of 26 family members confirmed th at the homozygous H42R mutation was completely associated with the ons et of NKH. The availability of DNA testing facilitates the prenatal di agnosis of NKH and the identification of carriers, which is necessary for genetic counseling in the affected families.