Novel mutations in the P-protein (glycine decarboxylase) gene in patients with glycine encephalopathy (non-ketotic hyperglycinemia)

Toone, Jennifer R.; Applegarth, Derek A.; Kure, Shigeo; Coulter‐Mackie, Marion B.; Sazegar, Payam; Kojima, Kanako; Ichinohe, Akiko

doi:10.1016/s1096-7192(02)00041-0

Cited by 20 publications

(17 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The GLDC mutations reported to date include the S564I mutation that is prevalent in Finnish patients , the R515S mutation found in 5% of Caucasian patients [Toone et al, 2000], microdeletions , large deletions [Takayanagi et al, 2000;Sellner et al, 2005], one abnormal splicing [Flusser et al, 2005], one nonsense mutation [Sellner et al, 2005], and 10 missense mutations [Toone et al, 2002;Korman et al, 2004;Kure et al, 2004;Boneh et al, 2005;Dinopoulos et al, 2005]. The AMT gene (MIM] 238310) mutations identified to date include nine missense mutations [Nanao et al, 1994[Nanao et al, , 1994aKure et al, 1998;Toone et al, 2000Toone et al, , 2001Toone et al, , 2003], one microdeletion [Kure et al, 1998[Kure et al, , 1998b, and one splicing mutation [Toone et al, 2000].…”

Section: Introductionmentioning

confidence: 99%

Comprehensive mutation analysis ofGLDC,AMT, andGCSHin nonketotic hyperglycinemia

et al. 2006

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Introductionmentioning

confidence: 99%

Comprehensive mutation analysis ofGLDC,AMT, andGCSHin nonketotic hyperglycinemia

et al. 2006

Self Cite

View full text Add to dashboard Cite

show abstract

“…The p.R515S mutation found in 5% of 50 non-Finnish NKH alleles (Toone et al 2001), and the p.S564I and p.G761R mutations identified in 70% and 8% of Finnish NKH alleles, respectively (Kure et al 1999), were not identified in our patients. The different ethnic backgrounds could explain differences in the distribution of mutations even though some Hispanic and mixed northern European were previously studied (Toone et al 2002).…”

Section: Resultsmentioning

confidence: 99%

“…A pseudo-gene (ψGLDC) has been localized to chromosome 4, shares 97.5% homology with the coding sequence, of functional GLDC gene, has no intronic sequence, and is not transcribed (Takayanagi et al 2000). About 50 different mutations of the GLDC gene have been found to date (Applegarth and Toone 2004;Kure et al 2003;Toone et al 2002Toone et al , 2003, although many changes have not been proved to be deleterious and most of them were not published (Applegarth and Toone 2004). We report the molecular investigation of the GLDC gene using a preliminary screening by denaturing high-performance liquid chromatography (DHPLC) in a series of 28 unrelated patients with neonatal NKH.…”

mentioning

confidence: 99%

Genetic heterogeneity of the GLDC gene in 28 unrelated patients with glycine encephalopathy

Conter

Rolland

Cheillan

et al. 2006

J of Inher Metab Disea

View full text Add to dashboard Cite

Glycine encephalopathy, or nonketotic hyperglycinaemia (NKH; Mckusick 238300) is a severe autosomal recessive disease due to a defect in the glycine cleavage system (GCS), which is a complex of four subunits: P-, T-, H- and L-proteins. A P-protein (glycine decarboxylase or GLDC) deficiency was reported in about 80% of NKH patients. We performed mutation analysis of the complete coding sequence of the GLDC gene in 28 unrelated patients with neonatal NKH using denaturing high-performance liquid chromatography (DHPLC) and sequencing. Forty different gene alterations were identified, confirming the large molecular heterogeneity of the GLDC gene. Eighteen alterations were clearly disease-causing: two large deletions, four one-base deletions (c.28delC, c.1175delC, c.2186delC, c.2422delA), one 1-base insertion (c.1002_1003insT), one 4-base insertion (c.1285_1286insCAAA), one insertion/deletion (c.2153_2155delinsTCCTGGTTTA), five nonsense mutations (p.E153X, p.R236X, p.E270X, p.R337X, p.R424X) and four splice site mutations (c.861+1G > T, c.1402-1C > G, c.2316-1G > A, c.2919+1G > A). Additionally, we identified one intronic mutation outside the consensus splice sites (c.2838+5G > A) and 21 nucleotide substitutions leading to amino acid change (including three previously described mutations: p.T269M, p.R461Q, p.G771R), the pathogenicity of which should be confirmed by expression studies (p.S132W, p.Y138F, p.G171A, p.T187K, p.R212K, p.T269M, p.R373W, p.I440N, p.R461Q, p.N533Y, p.C644F, p.H651R, p.V705M, p.N732K, p.G771R, p.H775R, p.T830M, p.A841P, p.D880V, p.S957P and p.R966G). Mutation analysis allowed us to identify sequence alterations in both alleles for 19 patients and in one allele for 7 patients One patient was carrying three mutations (p.Y138F, p.T269M and p.E153X) and one patient was carrying two amino acid substitutions on the same allele (p.V705M and p.R212K) and an unidentified mutation on the other allele. No mutation could be found in two patients, suggesting possible defects in the H-protein or gene alterations that could not be identified by our technique. The potential use of genotype determination for prenatal diagnosis is emphasized.

show abstract

“…Only R515S, T269M and A389V mutations were found in a few alleles from patients tested in Europe and Canada; all others are private. Only one mutation in the GCSH gene has been reported [41]. Patients in whom no mutation or only one mutation has been found, despite sequencing of the P-, T-and H-protein genes, have been reported [42].…”

Section: Geneticsmentioning

confidence: 99%

Nonketotic Hyperglycinaemia (Glycine Encephalopathy)

Dulac

Rolland²

2012

Inborn Metabolic Diseases

View full text Add to dashboard Cite

Novel mutations in the P-protein (glycine decarboxylase) gene in patients with glycine encephalopathy (non-ketotic hyperglycinemia)

Cited by 20 publications

References 14 publications

Comprehensive mutation analysis ofGLDC,AMT, andGCSHin nonketotic hyperglycinemia

Comprehensive mutation analysis ofGLDC,AMT, andGCSHin nonketotic hyperglycinemia

Genetic heterogeneity of the GLDC gene in 28 unrelated patients with glycine encephalopathy

Nonketotic Hyperglycinaemia (Glycine Encephalopathy)

Contact Info

Product

Resources

About