Phenotype-Genotype Correlations of 13 Rare CYP21A2 Mutations Detected in 46 Patients Affected with 21-Hydroxylase Deficiency and in One Carrier
Autor: | Michel David, Rita Menassa, Yves Morel, Claudine Lecointre, Véronique Tardy, Anne Lienhardt-Roussie, Raja Brauner, V. Sulmont |
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Rok vydání: | 2010 |
Předmět: |
medicine.medical_specialty
Time Factors Protein Conformation Endocrinology Diabetes and Metabolism Genetic counseling In silico Blotting Western Clinical Biochemistry Context (language use) medicine.disease_cause Biochemistry Endocrinology Internal medicine Chlorocebus aethiops Genotype medicine Animals Humans Genetic Predisposition to Disease Congenital adrenal hyperplasia Cells Cultured Genetic Association Studies Genetics Mutation Adrenal Hyperplasia Congenital biology 17-alpha-Hydroxyprogesterone Biochemistry (medical) 21-Hydroxylase medicine.disease Phenotype COS Cells biology.protein Steroid 21-Hydroxylase |
Zdroj: | The Journal of Clinical Endocrinology & Metabolism. 95:1288-1300 |
ISSN: | 1945-7197 0021-972X |
Popis: | Context: Steroid 21-hydroxylase deficiency is the most common enzymatic defect causing congenital adrenal hyperplasia with genotype/phenotype relationships for common mutations. Novel mutations of the CYP21A2 gene must be well studied to propose right genetic counseling for patients.Objective: Thirteen CYP21 mutations have been studied. A detailed description of phenotype was performed for all mutations (p.I77T, p.L167P, p.I230T, p.R233K, p.G291S, p.G292D, p.E320K, p.R341P, p.R354H, p.R369W, p.R408C, p.G424S, and p.R426H). In vitro and in silico studies were performed only for those not previously described (p.L167P, p.I230T, p.R233K, p.G292D, p.E320K, and p.R369W).Results: Regarding phenotype, patients with 10 of these mutations had a classical form. A patient with isolated p.I230T presented with nonclassical form and a patient with the association p.I230T + p.V281L in cis presented with a more severe phenotype. The p.R233K mutation was detected in a carrier partner. A patient with p.R369W presented with an intermediate form. Functional studies showed that all mutations except p.I230T and p.R369W decreased enzyme activity more than p.P30L: severity of p.R369W was intermediate between p.P30L and p.V281L, and finally p.I230T was less severe than p.V281L. Mutation analysis in a three-dimensional model structure of the CYP21 protein explained the observed in vitro effects, severe mutations being implicated in important functional domains of the protein.Conclusion: According to phenotype and functional studies, 11 of the mutations described, except the isolated p.R369W and p.I230T, may be responsible for a severe phenotype underlying the necessity to manage children having them. The p.I230T is a nonclassical mutation, and for the p.R369W, we need more cases to precise its severity. |
Databáze: | OpenAIRE |
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