Comprehensive mutation analysis of GLDC, AMT, and GCSH in nonketotic hyperglycinemia.

21st COE Program ‘‘Comprehensive Researchand Education Center for Planning of Drug Development and Clinical Evaluation,’’ Tohoku University, Sendai, JapanCommunicated by Jan P. KrausNonketotic hyperglycinemia (NKH) is an inborn error of metabolism characterized by accumulation of glycine inbodyfluidsand variousneurological symptoms. NKH iscausedby deficiency ofthe glycine cleavagemulti-enzymesystem with three specific components encoded by GLDC, AMT,andGCSH.Weundertookthefirstcomprehensive screening for GLDC, AMT,andGCSH mutations in 69 families (56, six, and seven families withneonatal, infantile, and late-onset type NKH, respectively). GLDC or AMT mutations were identified in 75% ofneonatal and 83% of infantile families, but not in late-onset type NKH. No GCSH mutation was identified in thisstudy. GLDC mutations were identified in 36 families, and AMT mutations were detected in 11 families. In 16 ofthe 36 families with GLDCmutations,mutationswereidentified inonlyonealleledespitesequencingoftheentirecoding regions. The GLDC gene consists of 25 exons. Seven of the 32 GLDC missense mutations were clusteredin exon 19, which encodes the cofactor-binding site Lys754. A large deletion involving exon 1 of the GLDC genewas found in Caucasian, Oriental, and black families. Multiple origins of the exon 1 deletion were suggested byhaplotype analysis with four GLDC polymorphisms. This study provides a comprehensive picture of the geneticbackground of NKH as it is known to date. Hum Mutat 27(4), 343–352, 2006.