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Ten novel HMGCL mutations in 24 patients of different origin with 3‐hydroxy‐3‐methyl‐glutaric aciduria
Author(s) -
Menao Sebastián,
LópezViñas Eduardo,
Mir Cecilia,
Puisac Beatriz,
Gratacós Esther,
Arnedo María,
Carrasco Patricia,
Moreno Susana,
Ramos Mónica,
Gil María Concepción,
Pié Ángeles,
Ribes Antonia,
PérezCerda Celia,
Ugarte Magdalena,
Clayton Peter T.,
Korman Stanley H.,
Serra Dolors,
Asins Guillermina,
Ramos Feliciano J.,
GómezPuertas Paulino,
Hegardt Fausto G.,
Casals Nuria,
Pié Juan
Publication year - 2009
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.20966
Subject(s) - missense mutation , biology , genetics , nonsense mutation , allele , genotype , mutation , gene
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.” © 2009 Wiley‐Liss, Inc.