The GLDC gene on chromosome 9p24.1 provides instructions for making an enzyme called Glycine Dehydrogenase. This protein consists of 1,020 amino acids and weighs about 113 kDa. Glycine dehydrogenase enzyme is one of four mitochondrial proteins (P, H, T, and L) that make a large complex called glycine cleavage enzyme that catalyzes the degradation of glycine. Degradation of excess glycine is necessary for the normal development and function of nerve cells in the brain and spinal cord.
Defects in the glycine dehydrogenase enzyme result in building up of excess amounts of glycine in the brain and spinal cord. Glycine build up causes intellectual disability, seizures, and breathing difficulties characteristic of glycine encephalopathy disease.
The GLDC gene consists of 25 coding exons and its length is approximately 113 kb. More than 40 mutations have been identified in this gene in patients with glycine encephalopathy disease. These mutations account for 80% of all cases of the disease. The most common mutations are caused by single amino acid substitutions. Also, insertion, deletion and splice site mutations have been reported to cause the disease. These mutations result in either production of a nonfunctional version of glycine dehydrogenase, or reduce but do not eliminate the enzyme's activity.
In eight patients with glycine encephalopathy, Boneh et al. (2005) identified a homozygous T>C transition within the ATG methionine codon in exon 1 of the GLDC gene, resulting in a met1>thr (p.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 five of six families were first cousins. Studies of two 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 nine affected members of a large consanguineous Bedouin kindred with atypical glycine encephalopathy, Flusser et al. (2005) identified a homozygous 2607C>A transversion in exon 22 of the GLDC gene, resulting in a silent substitution (p.pro869>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.
Al-Shamsi et al. (2014) undertook a study to calculate the birth prevalence of IEMs among Emiratis in the UAE by taking into consideration all neonates born with an inherited metabolic condition at Tawam Hospital between 1995 and 2012. In their study, Al-Shamsi et al. (2014) identified a novel mutation in the GLDC gene, c.1156G>C (p.D386H), resulting in Nonketotic Hyperglycinaemia.
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