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. More than 80% of the patients have defects in the gene encoding P-protein, 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 least 14 children were affected, and all the patients had seizures and respiratory failure within 2 days after birth. Enzymatic analysis revealed that T-protein activity was deficient in the liver specimen from one propositus. We screened this family for a mutation in the protein-coding region and exon/intron boundaries of T-protein gene by direct sequencing analysis. A missense mutation was found in exon 2; this resulted in an amino acid substitution from histidine to arginine at position 42 (H42R). Histidine 42 is conserved in human, bovine, chicken, pea, and Escherichia coli, suggesting that it has an important role in catalytic functions. Genotype analyses of 26 family members confirmed that the homozygous H42R mutation was completely associated with the onset of NKH. The availability of DNA testing facilitates the prenatal diagnosis of NKH and the identification of carriers, which is necessary for genetic counseling in the affected families.
Kure
S
S
Department of Biochemical Genetics, Tohoku University School of Medicine, Sendai, Japan. skure@mail.cc.tohoku.ac.jp
Mandel
H
H
Rolland
M O
MO
Sakata
Y
Y
Shinka
T
T
Drugan
A
A
Boneh
A
A
Tada
K
K
Matsubara
Y
Y
Narisawa
K
K
D000592:Amino Acid Metabolism, Inborn Errors / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics*; D019943:Amino Acid Substitution / Q000235:genetics*; D050960:Aminomethyltransferase; D018912:Arabs / Q000235:genetics; D001120:Arginine / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D005998:Glycine / Q000097:blood* / Q000235:genetics*; D006639:Histidine / Q000235:genetics; D006801:Humans; D019877:Hydroxymethyl and Formyl Transferases / Q000172:deficiency / Q000235:genetics*; D007231:Infant, Newborn; D007557:Israel / Q000208:ethnology; D008099:Liver / Q000201:enzymology / Q000473:pathology; D008297:Male; D009154:Mutation; D010375:Pedigree; D011296:Prenatal Diagnosis
D006639:Histidine; D001120:Arginine; D019877:Hydroxymethyl and Formyl Transferases; D050960:Aminomethyltransferase; D005998:Glycine