title: Comprehensive mutation analysis of GLDC, AMT, and GCSH in nonketotic hyperglycinemia.
abstract: Nonketotic hyperglycinemia (NKH) is an inborn error of metabolism characterized by accumulation of glycine in body fluids and various neurological symptoms. NKH is caused by deficiency of the glycine cleavage multi-enzyme system with three specific components encoded by GLDC, AMT, and GCSH. We undertook the first comprehensive screening for GLDC, AMT, and GCSH mutations in 69 families (56, six, and seven families with neonatal, infantile, and late-onset type NKH, respectively). GLDC or AMT mutations were identified in 75% of neonatal and 83% of infantile families, but not in late-onset type NKH. No GCSH mutation was identified in this study. GLDC mutations were identified in 36 families, and AMT mutations were detected in 11 families. In 16 of the 36 families with GLDC mutations, mutations were identified in only one allele despite sequencing of the entire coding regions. The GLDC gene consists of 25 exons. Seven of the 32 GLDC missense mutations were clustered in exon 19, which encodes the cofactor-binding site Lys754. A large deletion involving exon 1 of the GLDC gene was found in Caucasian, Oriental, and black families. Multiple origins of the exon 1 deletion were suggested by haplotype analysis with four GLDC polymorphisms. This study provides a comprehensive picture of the genetic background of NKH as it is known to date.
authors.affiliation: Department of Medical Genetics, Tohoku University School of Medicine, Sendai, Japan. skure@mail.tains.tohoku.ac.jp
authors.forename: Shigeo
authors.initials: S
authors.lastname: Kure
authors.forename: Kumi
authors.initials: K
authors.lastname: Kato
authors.forename: Agirios
authors.initials: A
authors.lastname: Dinopoulos
authors.forename: Chuck
authors.initials: C
authors.lastname: Gail
authors.forename: Ton J
authors.initials: TJ
authors.lastname: DeGrauw
authors.forename: John
authors.initials: J
authors.lastname: Christodoulou
authors.forename: Vladimir
authors.initials: V
authors.lastname: Bzduch
authors.forename: Rozalia
authors.initials: R
authors.lastname: Kalmanchey
authors.forename: Gyorgy
authors.initials: G
authors.lastname: Fekete
authors.forename: Alex
authors.initials: A
authors.lastname: Trojovsky
authors.forename: Barbara
authors.initials: B
authors.lastname: Plecko
authors.forename: Galen
authors.initials: G
authors.lastname: Breningstall
authors.forename: Jun
authors.initials: J
authors.lastname: Tohyama
authors.forename: Yoko
authors.initials: Y
authors.lastname: Aoki
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Matsubara
mesh_terms: D000293:Adolescent; D000483:Alleles; D000594:Amino Acid Oxidoreductases / Q000235:genetics*; D050960:Aminomethyltransferase / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005260:Female; D005820:Genetic Testing; D015894:Genome, Human / Q000235:genetics; D050841:Glycine Dehydrogenase (Decarboxylating) / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D020158:Hyperglycinemia, Nonketotic / Q000201:enzymology* / Q000235:genetics*; D007223:Infant; D007231:Infant, Newborn; D009097:Multienzyme Complexes / Q000235:genetics*; D011247:Pregnancy; D017384:Sequence Deletion / Q000235:genetics; D014166:Transferases / Q000235:genetics*
chemical_list: D002352:Carrier Proteins; D009097:Multienzyme Complexes; C064525:glycine cleavage system; D000594:Amino Acid Oxidoreductases; D050841:Glycine Dehydrogenase (Decarboxylating); D014166:Transferases; D050960:Aminomethyltransferase