Glutaryl-CoA dehydrogenase deficiency in Spain: Evidence of two groups of patients, genetically, and biochemically distinct
| Autor: | Busquets C, Merinero B, Christensen E, Gelpí JL, Campistol-Plana J, Pineda M, Fernández-Alvarez E, Prats JM, Sans A, Arteaga R, Martí M, Campos J, Martínez-Pardo M, Martínez-Bermejo A, Ruiz-Falcó ML, Vaquerizo J, Orozco M, Ugarte M, Coll MJ, Ribes A |
|---|---|
| Rok vydání: | 2000 |
| Předmět: |
Male
Oxidoreductases Acting on CH-CH Group Donors Molecular Sequence Data Glutaryl-CoA dehydrogenase Neural degeneration Glutaric aciduria type 1 Biology medicine.disease_cause Glutarates Gene Frequency Metabolic Diseases Genotype medicine Humans Amino Acid Sequence Alleles Genetics Mutation Polymorphism Genetic Glutaryl-CoA Dehydrogenase Single-strand conformation polymorphism medicine.disease Spain Inborn error of metabolism Pediatrics Perinatology and Child Health Female Oxidoreductases Sequence Alignment Glutaric Acidemia Type 1 |
| Zdroj: | PEDIATRIC RESEARCH r-FSJD: Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu Fundació Sant Joan de Déu Scopus-Elsevier r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu instname |
| ISSN: | 0031-3998 |
| Popis: | Glutaryl-CoA dehydrogenase (GCDH) deficiency causes glutaric aciduria type I (GA I), an inborn error of metabolism that is characterized clinically by dystonia and dyskinesia and pathologically by neural degeneration of the caudate and putamen. Studies of metabolite excretion allowed us to categorize 43 GA I Spanish patients into two groups: group 1 (26 patients), those presenting with high excretion of both glutarate and 3-hydroxyglutarate, and group 2 (17 patients), those who might not be detected by routine urine organic acid analysis because glutarate might be normal and 3-hydroxyglutarate only slightly higher than controls. Single-strand conformation polymorphism (SSCP) screening and sequence analysis of the 11 exons and the corresponding intron boundaries of the GCDH gene allowed us to identify 13 novel and 10 previously described mutations. The most frequent mutations in group 1 were A293T and R402W with an allele frequency of 30% and 28%, respectively. These two mutations were also found in group 2, but always in heterozygosity, in particular in combination with mutations V400M or R227P. Interestingly, mutations V400M and R227P were only found in group 2, and at least one of these mutations was found in 11 of 15 unrelated alleles, accounting together for 53% of the mutant alleles in group 2. Therefore, it seems clear that two genetically and biochemically distinct groups of patients exist. The severity of the clinical phenotype seems to be closely linked to the development of encephalopathic crises rather than to residual enzyme activity or genotype. Comparison of GCDH protein with other acyl-CoA dehydrogenases (whose x-ray crystal structure has been determined) reveals that most of the mutations identified in GCDH protein seem to affect folding and tetramerization, as has been described for a number of mutations affecting mitochondrial beta-oxidation acyl-CoA dehydrogenases. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|