Identification of a common mutation in Finnish patients with nonketotic hyperglycinemia

• Published in: The Journal of clinical investigation Vol. 90; no. 1; pp. 160 - 164
• Main Authors: KURE, S, TAKAYANAGI, M, NARISAWA, K, TADA, K, LEISTI, J
• Format: Journal Article
• Language: English
• Published: Ann Arbor, MI American Society for Clinical Investigation 01.07.1992
• Subjects: Amino Acid Metabolism, Inborn Errors - epidemiology; Amino Acid Metabolism, Inborn Errors - genetics; Amino Acid Sequence; Base Sequence; Biological and medical sciences; Finland - epidemiology; Genotype; Glycine - blood; Humans; Medical sciences; Metabolic diseases; Molecular Sequence Data; Mutation; Prevalence; Europe; Finland; Human; Messenger RNA; Multienzyme complex; Nucleotide sequence; Enzyme; Hyperglycinemia; Point mutation; Metabolic diseases; Glycine decarboxylase; Gene expression; Glycine; Enzymopathy
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI115831

Nonketotic hyperglycinemia (NKH) is an autosomal recessive metabolic disorder caused by the defects in the glycine cleavage system (GCS; EC 2.1.2.10), a multienzyme system that consists of four individual components. NKH is a rare disorder in many countries, but with a very high incidence in northern Finland. To understand the genetic background of this high incidence, we examined the GCS in a typical case of NKH at the molecular level. The activity of P protein, a component of the GCS, was not detected in the lymphoblasts of the patient, while P protein mRNA of a normal size and level was present in the cells. Structural analysis of P protein mRNA from the patient revealed a single nucleotide substitution from G to T in the protein coding region, which resulted in an amino acid alteration from Ser564 to Ile564. No P protein activity was detected when the mutant P protein with this amino acid substitution was expressed in COS 7 cells. The patient was homozygous for this mutation. Furthermore, this mutation was present in 70% (14 of 20) of P protein gene alleles in Finnish patients with NKH, whereas it was not found in 20 alleles of non-Finnish patients. The results suggest that this mutation is responsible for the high incidence of NKH in Finland.