Isolated 3-methylcrotonyl-CoA carboxylase deficiency: evidence for an allele-specific dominant negative effect and responsiveness to biotin therapy
| Autor: | David Valle, Terttu Suormala, Boris Gebhardt, Georg F. Hoffmann, M. Fernanda Dantas, Matthias R. Baumgartner, Cecilia Giunta, Dolores Friebel, Brian Fowler, Shlomo Almashanu, E. Regula Baumgartner |
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| Přispěvatelé: | University of Zurich, Baumgartner, Matthias R |
| Rok vydání: | 2004 |
| Předmět: |
Male
Mitochondrial Diseases DNA Mutational Analysis Gene Expression Loss of heterozygosity chemistry.chemical_compound 0302 clinical medicine Biotin Germany Missense mutation Genetics(clinical) Genetics (clinical) 0303 health sciences Psychomotor retardation Greece Reverse Transcriptase Polymerase Chain Reaction food and beverages Articles 3-Methylcrotonyl-CoA carboxylase deficiency Pyruvate carboxylase Carbon-Carbon Ligases medicine.symptom 2716 Genetics (clinical) medicine.medical_specialty Genetic Vectors Molecular Sequence Data Glycine 610 Medicine & health Biology Transfection 03 medical and health sciences 1311 Genetics 030225 pediatrics Internal medicine Genetics medicine Valerates Humans Allele Alleles 030304 developmental biology Newborn screening Base Sequence Dose-Response Relationship Drug Infant Newborn Sequence Analysis DNA Fibroblasts medicine.disease Endocrinology chemistry 10036 Medical Clinic Mutation |
| Zdroj: | American journal of human genetics. 75(5) |
| ISSN: | 0002-9297 |
| Popis: | Deficiency of 3-methylcrotonyl-CoA carboxylase (MCC) results in elevated excretion of 3-methylcrotonylglycine (3-MCG) and 3-hydroxyisovaleric acid (3-HIVA). MCC is a heteromeric mitochondrial enzyme comprising biotin-containing alpha subunits and smaller beta subunits, encoded by MCCA and MCCB, respectively. Mutations in these genes cause isolated MCC deficiency, an autosomal recessive disorder with a variable phenotype that ranges from severe neonatal to asymptomatic adult forms. No reported patients have responded to biotin therapy. Here, we describe two patients with a biochemical and, in one case, clinical phenotype of MCC deficiency, both of whom were responsive to biotin. The first patient presented at 3 months with seizures and progressive psychomotor retardation. Metabolic investigation at 2 years revealed elevated excretion of 3-MCG and 3-HIVA, suggesting MCC deficiency. High-dose biotin therapy was associated with a dramatic reduction in seizures, normalization of the electroencephalogram, and correction of the organic aciduria, within 4 weeks. MCC activity in fibroblasts was 25% of normal levels. The second patient, a newborn detected by tandem-mass-spectrometry newborn screening, displayed the same biochemical phenotype and remained asymptomatic with biotin up to the age of 18 months. In both patients, sequence analysis of the complete open reading frames of MCCA and MCCB revealed heterozygosity for MCCA-R385S and for the known polymorphic variant MCCA-P464H but revealed no other coding alterations. MCCA-R385S is unusual, in that it has a normal amount of MCC alpha protein but confers no MCC activity. We show that MCCA-R385S, but not other MCCA missense alleles, reduces the MCC activity of cotransfected MCCA-wild-type allele. Our results suggest that MCCA-R385S is a dominant negative allele and is biotin responsive in vivo. |
| Databáze: | OpenAIRE |
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