A Radha Rama Devi1, Vakkalagadda A Ramesh2, H A Nagarajaram3, S P S Satish4, U Jayanthi4, Lokesh Lingappa5. 1. Genetic Metabolic Unit, Rainbow Children Hospital, India; Sandor Life Sciences, India. Electronic address: radharamadevi@gmail.com. 2. Laboratory of Computational Biology, CDFD, Gruhakalpa, Nampally, Hyderabad, India; Graduate Studies, Manipal University, India. 3. Laboratory of Computational Biology, CDFD, Gruhakalpa, Nampally, Hyderabad, India. 4. Sandor Life Sciences, India. 5. Pediatric Neurology, Rainbow Children Hospital, India.
Abstract
BACKGROUND: Glutaric aciduria type I is an autosomal recessive organic acid disorder. The primary defect is the deficiency of Glutaryl-CoA dehydrogenase (EC number 1.3.99.7) enzyme that is involved in the catabolic pathways of the amino acids l-lysine, l-hydroxylysine, and l-tryptophan. It is a treatable neuro-metabolic disorder. Early diagnosis and treatment helps in preventing brain damage. METHODS: The Glutaryl-CoA dehydrogenase gene (GCDH) gene was sequenced to identify disease causing mutations by direct sequencing of all the exons in twelve patients who were biochemically confirmed with GA I. RESULTS: We identified eleven mutations of which nine are homozygous mutations, one heterozygous and two synonymous mutations. Among the eleven mutations, four mutations p.Q162R, p.P286S, p.W225X in two families and p.V410M are novel. A milder clinical presentation is observed in those families who are either heterozygous or with a benign synonymous SNP. Multiple sequence alignment (MSA) of GCDH with its homologues revealed that the observed novel mutations are not tolerated by protein structure and function. CONCLUSIONS: The present study indicates genetic heterogeneity in GCDH gene mutations among South Indian population. Genetic analysis is useful in prenatal diagnosis and prevention. Mutation analysis is a useful tool in the absence of non-availability of enzyme assay in GA I.
BACKGROUND:Glutaric aciduria type I is an autosomal recessive organic acid disorder. The primary defect is the deficiency of Glutaryl-CoA dehydrogenase (EC number 1.3.99.7) enzyme that is involved in the catabolic pathways of the amino acids l-lysine, l-hydroxylysine, and l-tryptophan. It is a treatable neuro-metabolic disorder. Early diagnosis and treatment helps in preventing brain damage. METHODS: The Glutaryl-CoA dehydrogenase gene (GCDH) gene was sequenced to identify disease causing mutations by direct sequencing of all the exons in twelve patients who were biochemically confirmed with GA I. RESULTS: We identified eleven mutations of which nine are homozygous mutations, one heterozygous and two synonymous mutations. Among the eleven mutations, four mutations p.Q162R, p.P286S, p.W225X in two families and p.V410M are novel. A milder clinical presentation is observed in those families who are either heterozygous or with a benign synonymous SNP. Multiple sequence alignment (MSA) of GCDH with its homologues revealed that the observed novel mutations are not tolerated by protein structure and function. CONCLUSIONS: The present study indicates genetic heterogeneity in GCDH gene mutations among South Indian population. Genetic analysis is useful in prenatal diagnosis and prevention. Mutation analysis is a useful tool in the absence of non-availability of enzyme assay in GA I.
Authors: Nikolas Boy; Chris Mühlhausen; Esther M Maier; Jana Heringer; Birgit Assmann; Peter Burgard; Marjorie Dixon; Sandra Fleissner; Cheryl R Greenberg; Inga Harting; Georg F Hoffmann; Daniela Karall; David M Koeller; Michael B Krawinkel; Jürgen G Okun; Thomas Opladen; Roland Posset; Katja Sahm; Johannes Zschocke; Stefan Kölker Journal: J Inherit Metab Dis Date: 2016-11-16 Impact factor: 4.982