Ten novel HMGCL mutations in 24 patients of different origin with 3-hydroxy-3-methyl-glutaric aciduria.
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."
Menao
Sebastián
S
Laboratory of Clinical Genetics and Functional Genomics, Department of Pharmacology-Physiology, Medical School, University of Zaragoza, Zaragoza, Spain.
López-Viñas
Eduardo
E
Mir
Cecilia
C
Puisac
Beatriz
B
Gratacós
Esther
E
Arnedo
María
M
Carrasco
Patricia
P
Moreno
Susana
S
Ramos
Mónica
M
Gil
María Concepción
MC
Pié
Angeles
A
Ribes
Antonia
A
Pérez-Cerda
Celia
C
Ugarte
Magdalena
M
Clayton
Peter T
PT
Korman
Stanley H
SH
Serra
Dolors
D
Asins
Guillermina
G
Ramos
Feliciano J
FJ
Gómez-Puertas
Paulino
P
Hegardt
Fausto G
FG
Casals
Nuria
N
Pié
Juan
J
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
D015093:Meglutol; D007652:Oxo-Acid-Lyases; C021410:3-hydroxy-3-methylglutaryl-coenzyme A lyase