Alternative titles; symbols
HGNC Approved Gene Symbol: GLDC
SNOMEDCT: 237939006; ICD10CM: E72.51;
Cytogenetic location: 9p24.1 Genomic coordinates (GRCh38) : 9:6,532,467-6,645,729 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9p24.1 | Glycine encephalopathy1 | 605899 | Autosomal recessive | 3 |
The enzyme system for cleavage of glycine (glycine cleavage system; GCS; EC 2.1.2.10), which is confined to the mitochondria, is composed of 4 protein components: P protein (a pyridoxal phosphate-dependent glycine decarboxylase), H protein (a lipoic acid-containing protein, 238330), T protein (a tetrahydrofolate-requiring enzyme, 238310), and L protein (a lipoamide dehydrogenase, 238331).
Kume et al. (1991) cloned the cDNA encoding human glycine decarboxylase, P protein. The deduced protein contains 1,020 amino acids. By RNA blot analysis, Takayanagi et al. (2000) demonstrated that GLDC is expressed in human liver, kidney, brain, and placenta. By dot-blot analysis, Kure et al. (2001) detected expression of GLDC in a limited number of tissues with strong expression in liver, placenta, and kidney; moderate expression in brain, small intestine, thyroid gland, and pituitary gland; and weak expression in colon, bladder, and lung.
Takayanagi et al. (2000) determined the structure of the GLDC gene and its pseudogene. The GLDC gene spans at least 135 kb and contains 25 exons. All donor and acceptor sites adhered to the canonical GT-AG rule, except for the donor site of intron 21, where a variant form GC is used instead of GT. By primer extension analysis, the transcription initiation site was assigned to a residue 163 bp upstream from the translation initiation triplet. The GLDC pseudogene has no introns and shares 97.5% homology with the coding region of functional GLDC, suggesting that it is a processed pseudogene that arose from the GLDC transcript about 4 to 8 million years ago.
Kim et al. (2015) identified a key role for serine and glycine metabolism in the survival of brain cancer cells within the ischemic zones of gliomas. In human glioblastoma multiforme (137800), SHMT2 (138450) and GLDC are highly expressed in the pseudopalisading cells that surround necrotic foci. Kim et al. (2015) found that SHMT2 activity limits that of PKM2 (179050) and reduces oxygen consumption, eliciting a metabolic state that confers a profound survival advantage to cells in poorly vascularized tumor regions. GLDC inhibition impairs cells with high SHMT2 levels, as the excess glycine not metabolized by GLDC can be converted to the toxic molecules aminoacetone and methylglyoxal. Kim et al. (2015) concluded that SHMT2, which is required for cancer cells to adapt to the tumor environment, also renders these cells sensitive to glycine cleavage system inhibition.
Bodkin et al. (2019) conducted a proof-of-principle clinical trial on a mother and son with a complex rearrangement of chromosome 9p24 that included triplication of the GLDC gene (Grochowski et al., 2018). The mother had been diagnosed with bipolar disorder with psychotic features, and the son with schizoaffective disorder. As triplication of GLDC could be expected to result in low levels of brain glycine and D-serine, causing hypofunctioning of the NMDAR receptor channel, Bodkin et al. (2019) undertook the trial to determine whether augmentation of usual psychotropic drug treatment with glycine, a full agonist at the NMDAR glycine modulatory site (GMS), reduced psychotic and mood symptoms in these 2 carriers. Bodkin et al. (2019) performed 2 double-blind placebo-controlled trials in both patients, keeping all other psychotropic medications stable throughout the 6-week trials: one of supplemental glycine at a target dose of 0.8 gm/kg/day, and one of D-cycloserine. Both agents resulted in improved psychotic and mood symptoms in both patients. Glycine dosing at the proposed level was not well tolerated, but was well tolerated and effective at 0.6 gm/kg/day.
A high frequency of glycine encephalopathy (GCE1; 605899) has been found in some counties of Finland (von Wendt and Simila, 1980). In 13 heterozygotes in Finland, von Wendt et al. (1981) found minor dysfunctions of the central nervous system which they suggested may be due to a slightly abnormal degradation of glycine (which has a neurotransmitter role). In a patient with GCE, Kure et al. (1992) identified homozygosity for a G to T in the protein coding region of the GLDC gene, which resulted in an amino acid alteration from serine-564 to isoleucine (S564I; 238300.0001). Kure et al. (1992) found that 14 of 20 P protein alleles in Finnish patients carried this single nucleotide substitution.
Using the GCSP cDNA as a probe in Southern blot analysis of genomic DNA from 2 patients with nonketotic hyperglycinemia, Tada et al. (1990) showed that they had a specific defect in P protein, namely, a partial deletion.
Toone et al. (2000) identified a recurrent mutation in the P protein, R515S (238300.0004), in 2 unrelated patients with glycine encephalopathy.
In patients with glycine encephalopathy, Applegarth and Toone (2001) confirmed 9 mutations in the T protein (AMT; 238310) and 8 mutations in the P protein. They also reviewed 7 cases of transient NKH.
Kure et al. (2006) undertook a comprehensive screening for mutations in the P, T, and H enzymes in 69 families (56, 6, and 7 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 1 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, Asian, and black families. Multiple origins of the exon 1 deletion were suggested by haplotype analysis with 4 GLDC polymorphisms.
Burton et al. (1989) observed nonketotic glycinemia in an infant with the metabolic and chromosomal features of the 9p- syndrome, leading them to suggest that a gene for nonketotic glycinemia may be located on the short arm of chromosome 9. By fluorescence in situ hybridization using genomic clones, Isobe et al. (1994) assigned the functional GCSP gene to 9p24-p23 and a processed pseudogene to 4q12. Sakakibara et al. (1990) had found deletion of the 5-prime region of the GCSP gene in a patient with glycine encephalopathy.
Sakata et al. (2001) reported the structure and expression of the glycine cleavage system in the rat central nervous system.
Glycine encephalopathy (GCE1; 605899) is said to have an incidence of 1 in 12,000 births in northern Finland (von Wendt et al., 1979). Kure et al. (1992) demonstrated that the defect is in the P protein and that a G-to-T mutation resulting in substitution of isoleucine for serine-564 accounts for 14 of 20 P protein alleles. Activity of P protein was undetectable in the lymphoblasts, while P protein mRNA of a normal size and level was present. The S564I mutation was found in homozygous state in 5 patients, while 4 other patients were probably compound heterozygotes.
In a Japanese patient with glycine encephalopathy (GCE1; 605899), Kure et al. (1992) found deletion of phenylalanine-756 in the GLDC gene. Phe756 is located close to lys754, the binding site of pyridoxal phosphate (Kure et al. (1991, 1992)). The deletion probably interferes with B6 binding or function.
Takayanagi et al. (2000) studied a Japanese boy with glycine encephalopathy (GCE1; 605899) of neonatal onset. The parents were not known to be related and were from the Aichi prefecture in the central area of Japan. Convulsive seizures and respiratory distress developed at 3 days of age. Administration of ketamine improved his electroencephalographic findings and hyperirritability. His psychomotor development was, however, severely delayed. He never gained head control or walked, and joint contractures developed. At 9 years of age he died of influenzal pneumonia and renal failure. An enzymatic analysis of an autopsied liver specimen revealed that he was completely deficient in GLDC activity. Takayanagi et al. (2000) found that exons 1-3 of the functional GLDC gene from this patient were not amplified by PCR, whereas those from control subjects were. These results suggested a large homozygous deletion (at least 30 kb) in the patient. Takayanagi et al. (2000) devised a semiquantitative PCR to estimate the number of GLDC alleles by using the pseudogene as an internal control and confirmed the homozygosity and heterozygosity of the deletion in the patient and his parents, respectively.
In 2 patients with glycine encephalopathy (GCE1; 605899), Toone et al. (2000) identified a G-to-C transversion leading to an arg-to-ser substitution at codon 515 in the GLDC gene. This mutation was not identified in any of 100 normal alleles, and the arginine at this residue was conserved in all species for which sequence was available from human to E. coli.
Toone et al. (2001) reported that the R515S mutation is present in 5% of NKH alleles.
Applegarth and Toone (2001) reported that this mutation in glycine encephalopathy (GCE1; 605899), reported originally by Kure et al. (1999), is present in 8% of NKH Finnish alleles.
In 4 affected patients from 2 unrelated families with glycine encephalopathy (GCE1; 605899), Korman et al. (2004) identified a homozygous 2405C-T transition in exon 20 of the GLDC gene, resulting in an ala802-to-val (A802V) substitution at a highly conserved residue. Functional expression studies of the mutation in COS-7 cells showed that mutant protein activity was reduced to 32% of control levels. The authors noted that 32% residual activity is markedly different from the S564I mutation (238300.0001), which has virtually no enzyme activity. The phenotype of the affected patients with the A802V mutation was unique: 3 patients from 1 family had complete resolution of symptoms and developed normally, whereas the fourth patient had only mild neurologic sequelae.
In 8 Arab patients with glycine encephalopathy (GCE1; 605899), Boneh et al. (2005) identified a homozygous T-to-C transition within the ATG methionine codon in exon 1 of the GLDC gene, resulting in a met1-to-thr (M1T) substitution within the initiation codon. All obligate carriers were heterozygous for the mutation and 122 control alleles did not have the mutation. The parents of patients in 5 of 6 families were first cousins. Studies of 2 patients showed markedly decreased GLDC mRNA levels and absence of enzyme activity. All the patients originated from an isolated population of approximately 5,000 people in a small village near Jerusalem.
In 2 unrelated patients with a mild form of glycine encephalopathy (GCE1; 605899), Dinopoulos et al. (2005) identified a homozygous 1166C-T transition in exon 9 of the GLDC gene, resulting in an ala389-to-val (A389V) substitution. Functional expression studies showed that the mutant enzyme retained 7.9% residual activity, which may explain the milder phenotype.
In a patient with a mild form of glycine encephalopathy (GCE1; 605899), Dinopoulos et al. (2005) identified a homozygous 2216A-G transition in the GLDC gene, resulting in an arg739-to-his (R739H) substitution. Functional expression studies showed that the mutant enzyme retained 6.1% residual activity, which may explain the milder phenotype.
In 9 affected members of a large consanguineous Israeli Bedouin kindred with atypical glycine encephalopathy (GCE1; 605899), Flusser et al. (2005) identified a homozygous 2607C-A transversion in exon 22 of the GLDC gene, resulting in a silent substitution (pro869 to pro) that affects a splice site. A patient lymphoblast cell line showed abnormal GLDC DNA fragments and significantly reduced mRNA levels, consistent with a pathogenic mutation. An additional unrelated patient had the same mutation.
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