Molecular genetic study of glutaric aciduria, type I: Identification of a novel mutation

Abstract

Glutaric acidemia type I (GA-1) is an inborn error of metabolism due to deficiency of glutaryl-CoA dehydrogenase (GCDH), which catalyzes the conversion of glutaryl-CoA to crotonyl-CoA. GA-1 occurs in about 1 in 100 000 infants worldwide. The GCDH gene is on human chromosome 19p13.2, spans about 7 kb and comprises 11 exons and 10 introns. Tandem mass spectrometry (MS/MS) was used for clinical diagnosis in a proband from Iran with GA-1. Sanger sequencing was performed using primers specific for coding exons and exon-intron flanking regions of the GCDH gene in the proband. Cosegregation analysis and in silico assessment were performed to confirm the pathogenicity of the candidate variant. A novel homozygous missense variant c.1147C > A (p.Arg383Ser) in exon 11 of GCDH was identified. Examination of variant through in silico software tools determines its deleterious effect on protein in terms of function and stability. The variant cosegregates with the disease in family. In this study, the clinical and molecular aspects of GA-1 were investigated, which showed one novel mutation in the GCDH gene in an Iranian patient. The variant is categorized as pathogenic according to the the guideline of the American College of Medical Genetics and Genomics (ACMG) for variant interpretation. This mutation c.1147C > A (p.Arg383Ser) may also be prevalent among Iranian populations.

Pathogenesis of brain damage in glutaric acidemia type I: Lessons from the genetic mice model

“…Glutaric acidemia type I (GA I; OMIM # 231,670) is an inherited autosomal recessive neurometabolic disease caused by mutations in the gene encoding the mitochondrial enzyme glutaryl‐CoA dehydrogenase (GCDH; EC 1.3.99.7) of the catabolic pathway of the amino acids lysine (Lys), hydroxylysine and tryptophan (Goodman et al, 1977). The GCDH gene is located on human chromosome 19p13.2, spans about 7 kb and comprises 11 exons and 10 introns (Goodman et al, 1977; Shadmehri et al, 2019). GCDH catalyzes the dehydrogenation of glutaryl‐CoA to glutaconyl‐CoA and its decarboxylation to crotonyl‐CoA.…”

Rhabdomyolysis, Acute Kidney Injury, and a Novel Frameshift Mutation in a Child with Glutaric Acidemia Type I

“…The GCDH gene is mapped to chromosome 19p13.2, and >200 disease-causing GCDH mutations have been reported in the Human Gene Mutation Database (HGMD), with racial differences in the types of mutations [1][2][3][4]. The gene mutations in this patient were c.383G>A (p.R128Q) and c.873delC (p.N291Kfs*41), which were inherited from her father and mother, respectively.…”

A novel mutation in the glutaryl‐CoA dehydrogenase gene (GCDH) in an Iranian patient affected with Glutaric acidemia type 1

“…They suggested, it may be prevalent among Iranian populations. 23 In 2019, Zayed et al studied 41 Egyptian patients with GA1. They identified a total of 25 variants, of which the following six novel variants were identified.…”

“…In 2019, Ahmadi Shadmehri et al investigated clinical and molecular aspects of GA‐1 in one Iranian patient and showed one novel pathogenic mutation in the GCDH gene: c.1147C > A (p. Arg383Ser). They suggested, it may be prevalent among Iranian populations 23 . In 2019, Zayed et al studied 41 Egyptian patients with GA1.…”