title: New case of mitochondrial HMG-CoA synthase deficiency. Functional analysis of eight mutations.
abstract: Mitochondrial HMG-CoA synthase deficiency is a rare inherited metabolic disorder that affects ketone-body synthesis. Acute episodes include vomiting, lethargy, hepatomegaly, hypoglycaemia, dicarboxylic aciduria, and in severe cases, coma. This deficiency may have been under-diagnosed owing to the absence of specific clinical and biochemical markers, limitations in liver biopsy and the lack of an effective method of expression and enzyme assay for verifying the mutations found. To date, eight patients have been reported with nine allelic variants of the HMGCS2 gene. We present a new method of enzyme expression and a modification of the activity assay that allows, for first time, the functional study of missense mutations found in patients with this deficiency. Four of the missense mutations (p.V54M, p.R188H, p.G212R and p.G388R) did not produce proteins that could have been detected in soluble form by western blot; three produced a total loss of activity (p.Y167C, p.M307T and p.R500H) and one, variant p.F174L, gave an enzyme with a catalytic efficiency of 11.5%. This indicates that the deficiency may occur with partial loss of activity of enzyme. In addition, we describe a new patient with this deficiency, in which we detected the missense allelic variant, c.1162G>A (p.G388R) and the nonsense variant c.1270C>T (p.R424X).
authors.affiliation: Unit of Clinical Genetics and Functional Genomics, Department of Pharmacology Physiology, Medical School, University of Zaragoza, Spain.
authors.forename: Mónica
authors.initials: M
authors.lastname: Ramos
authors.forename: Sebastián
authors.initials: S
authors.lastname: Menao
authors.forename: María
authors.initials: M
authors.lastname: Arnedo
authors.forename: Beatriz
authors.initials: B
authors.lastname: Puisac
authors.forename: María Concepción
authors.initials: MC
authors.lastname: Gil-Rodríguez
authors.forename: María Esperanza
authors.initials: ME
authors.lastname: Teresa-Rodrigo
authors.forename: María
authors.initials: M
authors.lastname: Hernández-Marcos
authors.forename: Germaine
authors.initials: G
authors.lastname: Pierre
authors.forename: Uma
authors.initials: U
authors.lastname: Ramaswami
authors.forename: Carolina
authors.initials: C
authors.lastname: Baquero-Montoya
authors.forename: Gloria
authors.initials: G
authors.lastname: Bueno
authors.forename: Cesar
authors.initials: C
authors.lastname: Casale
authors.forename: Fausto G
authors.initials: FG
authors.lastname: Hegardt
authors.forename: Paulino
authors.initials: P
authors.lastname: Gómez-Puertas
authors.forename: Juan
authors.initials: J
authors.lastname: Pié
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D004252:DNA Mutational Analysis; D004789:Enzyme Activation; D005091:Exons; D023061:Gene Order; D006801:Humans; D006904:Hydroxymethylglutaryl-CoA Synthase / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism*; D007003:Hypoglycemia / Q000201:enzymology* / Q000235:genetics*; D007223:Infant; D008297:Male; D008661:Metabolism, Inborn Errors / Q000201:enzymology* / Q000235:genetics*; D028361:Mitochondrial Diseases / Q000201:enzymology* / Q000235:genetics*; D008958:Models, Molecular; D009154:Mutation; D020125:Mutation, Missense; D011487:Protein Conformation
chemical_list: D006904:Hydroxymethylglutaryl-CoA Synthase
keywords: Ketone bodies; Mitochondrial HMG-CoA synthase deficiency; Mutations