title: Ten novel HMGCL mutations in 24 patients of different origin with 3-hydroxy-3-methyl-glutaric aciduria.
abstract: 3-Hydroxy-3-methylglutaric aciduria is a rare autosomal recessive genetic disorder that affects ketogenesis and L-leucine catabolism. The clinical acute symptoms include vomiting, convulsions, metabolic acidosis, hypoketotic hypoglycaemia and lethargy. To date, 33 mutations in 100 patients have been reported in the HMGCL gene. In this study 10 new mutations in 24 patients are described. They include: 5 missense mutations: c.109G>A, c.425C>T, c.521G>A, c.575T>C and c.598A>T, 2 nonsense mutations: c.242G>A and c.559G>T, one small deletion: c.853delC, and 2 mutations in intron regions: c.497+4A>G and c.750+1G>A. Two prevalent mutations were detected, 109G>T (E37X) in 38% of disease alleles analyzed and c.504_505delCT in 10% of them. Although patients are mainly of European origin (71%) and mostly Spanish (54%), the group is ethnically diverse and includes, for the first time, patients from Pakistan, Palestine and Ecuador. We also present a simple, efficient method to express the enzyme and we analyze the possible functional effects of missense mutations. The finding that all identified missense mutations cause a >95% decrease in the enzyme activity, indicates that the disease appears only in very severe genotypes."
authors.affiliation: Laboratory of Clinical Genetics and Functional Genomics, Department of Pharmacology-Physiology, Medical School, University of Zaragoza, Zaragoza, Spain.
authors.forename: Sebastián
authors.initials: S
authors.lastname: Menao
authors.forename: Eduardo
authors.initials: E
authors.lastname: López-Viñas
authors.forename: Cecilia
authors.initials: C
authors.lastname: Mir
authors.forename: Beatriz
authors.initials: B
authors.lastname: Puisac
authors.forename: Esther
authors.initials: E
authors.lastname: Gratacós
authors.forename: María
authors.initials: M
authors.lastname: Arnedo
authors.forename: Patricia
authors.initials: P
authors.lastname: Carrasco
authors.forename: Susana
authors.initials: S
authors.lastname: Moreno
authors.forename: Mónica
authors.initials: M
authors.lastname: Ramos
authors.forename: María Concepción
authors.initials: MC
authors.lastname: Gil
authors.forename: Angeles
authors.initials: A
authors.lastname: Pié
authors.forename: Antonia
authors.initials: A
authors.lastname: Ribes
authors.forename: Celia
authors.initials: C
authors.lastname: Pérez-Cerda
authors.forename: Magdalena
authors.initials: M
authors.lastname: Ugarte
authors.forename: Peter T
authors.initials: PT
authors.lastname: Clayton
authors.forename: Stanley H
authors.initials: SH
authors.lastname: Korman
authors.forename: Dolors
authors.initials: D
authors.lastname: Serra
authors.forename: Guillermina
authors.initials: G
authors.lastname: Asins
authors.forename: Feliciano J
authors.initials: FJ
authors.lastname: Ramos
authors.forename: Paulino
authors.initials: P
authors.lastname: Gómez-Puertas
authors.forename: Fausto G
authors.initials: FG
authors.lastname: Hegardt
authors.forename: Nuria
authors.initials: N
authors.lastname: Casals
authors.forename: Juan
authors.initials: J
authors.lastname: Pié
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D018912:Arabs / Q000235:genetics; D020134:Catalytic Domain / Q000235:genetics; D004252:DNA Mutational Analysis; D004484:Ecuador; D005060:Europe; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007700:Kinetics; D015093:Meglutol / Q000378:metabolism*; D008661:Metabolism, Inborn Errors / Q000208:ethnology / Q000235:genetics* / Q000473:pathology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D007652:Oxo-Acid-Lyases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D010154:Pakistan; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid
chemical_list: D015093:Meglutol; D007652:Oxo-Acid-Lyases; C021410:3-hydroxy-3-methylglutaryl-coenzyme A lyase