Genomic deletion within GLDC is a major cause of non-ketotic hyperglycinaemia

Abstract

Background: Non-ketotic hyperglycinaemia (NKH) is an inborn error of metabolism characterised by accumulation of glycine in body fluids and various neurological symptoms. NKH is caused by deficiency of the glycine cleavage multienzyme system with three specific components encoded by GLDC, AMT and GCSH. Most patients are deficient of the enzymatic activity of glycine decarboxylase, which is encoded by GLDC. Our recent study has suggested that there are a considerable number of GLDC mutations which are not identified by the standard exon-sequencing method. Methods: A screening system for GLDC deletions by multiplex ligation-dependent probe amplification (MLPA) has been developed. Two distinct cohorts of patients with typical NKH were screened by this method: the first cohort consisted of 45 families with no identified AMT or GCSH mutations, and the second cohort was comprised of 20 patients from the UK who were not prescreened for AMT mutations. Results: GLDC deletions were identified in 16 of 90 alleles (18%) in the first cohort and in 9 of 40 alleles (22.5%) in the second cohort. 14 different types of deletions of various lengths were identified, including one allele where all 25 exons were missing. Flanking sequences of interstitial deletions in five patients were determined, and Alu-mediated recombination was identified in three of five patients. Conclusions: GLDC deletions are a significant cause of NKH, and the MLPA analysis is a valuable first-line screening for NKH genetic testing.

Disruption of the Glycine Cleavage System Enables Sinorhizobium fredii USDA257 To Form Nitrogen-Fixing Nodules on Agronomically Improved North American Soybean Cultivars

“…The glycine cleavage system is the most important pathway in serine and glycine catabolism in various vertebrates including humans. Nonketotic hyperglycinemia, a genetic disorder characterized by abnormally high levels of glycine in human infants, results from defective glycine cleavage activity (18). It is not clear why inactivation of the glycine cleavage system of USDA257 enables this strain to nodulate soybean cultivar McCall.…”

Novel SLC7A7 large rearrangements in lysinuric protein intolerance patients involving the same AluY repeat

“…30 In fact, there are several inherited disorders for which Alu-mediated recombination is a common cause. 31 Given the high Alu density in introns 3, 5 and the 3 0 region, and the high degree of homology between Alu repeats, a recombination event could potentially occur anywhere within this region. However, the same AluY at the 3 0 region is involved in 38% (three out of eight) of all unrelated chromosomes with SLC7A7 large rearrangements described so far, 6 suggesting that it could be a recombination hot spot, as it has been observed at the duplication and deletion breakpoints in a number of human genetic diseases.…”

Structure of the Homodimeric Glycine Decarboxylase P-protein from Synechocystis sp. PCC 6803 Suggests a Mechanism for Redox Regulation

“…In humans, for example, such defects cause the inborn disease glycine encephalopathy (nonketotic hyperglycinemia), which leads to accumulation of glycine in the central nervous system. This terminal disease very often results from mutations in the P-protein-encoding gene (16) but can also be due to defective T-protein or H-protein genes (17). In plants, the artificial deletion of the two P-protein genes was lethal for seedlings of the model plant Arabidopsis thaliana during or shortly after germination (18).…”