Abstract
We have investigated the molecular lesions of T-protein deficiency causing typical or atypical nonketotic hyperglycinemia (NKH) in two unrelated pedigrees. A patient with typical NKH was identified as being homozygous for a missense mutation in the T-protein gene, a G-to-A transition leading to a Gly-to-Asp substitution at amino acid 269 (G269D). Sibling 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 is 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. coli. The mutation occurring in more conservative amino acid residues thus results in more deleterious damage to the T-protein, and gives the severe clinical phenotype, viz., typical NKH.
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References
Bachmann C, Mihatsch MJ, Baumgartner ER, Brechbühler T, Bühler UK, Olafsson A, Ohnacker H, Wick H (1971) Nichtketotische Hyperglyzinämie: perakuter Verlauf im Neugeborenenalter. Helv Paediatr Acta 26:228–243.
Barker D, Schafer M, White R (1984) Restriction sites containing CpG show a higher frequency of polymorphism in human DNA. Cell 36:131–138.
Coulondre C, Miller JH, Farabaugh PJ, Gilbert W (1978) Molecular basis of base substitution hotspots in Escherichia coli. Nature 274:775–780.
Haan EA, Kirby DM, Tada K, Hayasaka K, Danks DM (1986) Difficulties in assessing the effect of strychnine on the outcome of non-ketotic hyperglycinemia. Observations on sisters with a mild T-protein defect. Eur J Pediatr 145:267–270.
Hayasaka K, Tada K, Fueki N, Nakamura Y, Nyhan WL, Schmidt K, Packman S, Seashore MR, Haan E, Danks DM, Schutgens RBH (1987a) Nonketotic hyperglycinemia: analysis of glycine cleavage system in typical and atypical cases. J Pediatr 110:873–877.
Hayasaka K, Tada K, Fueki N, Takahashi I, Igarashi A, Takabayashi T, Baumgartner R (1987b) Feasibility of prenatal diagnosis of nonketotic hyperglycinemia: existence of the glycine cleavage system in placenta. J Pediatr 110:124–126.
Hayasaka K, Nanao K, Takada G, Okamura-Ikeda K, Motokawa Y (1993) Isolation and sequence determination of cDNA encoding human T-protein of the glycine cleavage system. Biochem Biophys Res Commun 192:766–771.
Kikuchi G (1973) The glycine cleavage system: composition, reaction mechanism, and physiologic significance. Mol Cell Biochem 1:169–187.
Kure S, Narisawa K, Tada K (1991) Structural and expression analyses of normal and mutant mRNA encoding glycine decarboxylase: three-base deletion in mRNA causes nonketotic hyperglycinemia. Biochem Biophys Res Commun 174:1176–1182.
Kure S, Takayanagi M, Narisawa K, Tada K, Leisiti J (1992) Identification of a common mutation in Finnish patients with nonketotic hyperglycinemia. J Clin Invest 90:160–164.
Nanao K, Takada G, Takahashi E, Seki N, Komatsu Y, Okamura-Ikeda K, Motokawa Y, Hayasaka K (1994) Structure and chromosomal localization of the gene encoding human T-protein of the glycine cleavage system. Genomics 19:27–30.
Nicoloso M, Qu LH, Bachellerie JP (1989) Titration of variant DNA sequences differing by a single point-mutation by selective dot-blot hybridization with synthetic oligonucleotide. Biochem Biophys Res Commun 159:1233–1241.
Nyhan WL (1989) Nonketotic hyperglycinemia. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic basis of inherited disease. Mcgraw-Hill, New York, pp 743–753.
Okamura-Ikeda K, Fujiwara K, Yamamoto M, Hiraga K, Motokawa Y (1991) Isolation and sequence determination of cDNA encoding T-protein of the glycine cleavage system. J Biol Chem 266:4917–4921.
Okamura-Ikeda K, Fujiwara K, Motokawa Y (1992) Molecular cloning of a cDNA encoding chicken T-protein of the glycine cleavage system and expression of the functional protein in Escherichia coli. J Biol Chem 267:18284–18290.
Okamura-Ikeda K, Ohmura Y, Fujiwara K, Motokawa Y (1993) Cloning and nucleotide sequence of the gcv operon encoding the Escherichia coli glycine cleavage system. Eur J Biochem 216:539–548.
Saiki RK, Gelfand DH, Stoffel S, Scharf SJ, Higuchi R, Horn GT, Mullis KB, Erlich HA (1988) Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science 239:487–491.
Sanger F, Nicklen S, Coulson AR (1977) DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci USA 74:5463–5467.
Von Wendt L, Simila S, Saukkonen AL, Koivisto M, Kouvalainen K (1981) Prenatal brain damage in nonketotic hyperglycinemia. Am J Dis Child 135:1072.
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Nanao, K., Okamura-Ikeda, K., Motokawa, Y. et al. Identification of the mutations in the T-protein gene causing typical and atypical nonketotic hyperglycinemia. Hum Genet 93, 655–658 (1994). https://doi.org/10.1007/BF00201565
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DOI: https://doi.org/10.1007/BF00201565