The gene HMGCL encodes 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) lyase. Mutations in HMG-CoA lyase cause HMG-CoA lyase deficiency (HMGCLD), which is an autosomal recessive congenital disorder of metabolism. This study was designed to detect mutation in the 3-hydroxy-3-methylglutaryl-CoA lyase (HMGCL) gene in a Saudi family segregating HMG-CoA lyase deficiency (HMGCLD).Methods: Clinical and molecular genetic analysis of a Saudi family with five individuals affected with HMGCLD was performed by GC-MS, tandem MS and sequencing. This study was conducted in the Centre for Genetics and Inherited Diseases, Taibah University Almadinah Almunawwarah, Saudi Arabia from September 2015 to February 2016. Sanger sequencing of the entire coding region and the intron-exon junctions of the HMGCL gene identified a recurrent missense mutation in exon 2. This mutation (c.122G>A) causes a substitution of a highly conserved amino acid Arginine to a Glutamine residue at position 41 (p.Arg41Gln). This is the most frequent mutation found in the HMGCL gene in Saudi population and might have occurred due to a founder effect. Multiple in silico software predicted this mutation as disease-causing. Moreover, to determine the protein stability upon change in amino acid various tools including SDM, I-Mutant, mCSM and DUET were used and found that the mutation, identified in this family, is protein destabilizing. An extensive literature review was performed and all mutations reported to date in the HMGCL gene were identified and listed.
Key words: HMGCL gene, 3-hydroxymethyl-3-methylglutaryl-CoA lyase (HMG-CoA lyase) deficiency, homozygous mutation, protein stability.
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