Clinical, genetic, and structural basis of congenital adrenal hyperplasia due to 11β-hydroxylase deficiency
- 22 February 2017
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 114 (10), E1933-E1940
- https://doi.org/10.1073/pnas.1621082114
Abstract
Congenital adrenal hyperplasia (CAH), resulting from mutations in CYP11B1, a gene encoding 11β-hydroxylase, represents a rare autosomal recessive Mendelian disorder of aberrant sex steroid production. Unlike CAH caused by 21-hydroxylase deficiency, the disease is far more common in the Middle East and North Africa, where consanguinity is common often resulting in identical mutations. Clinically, affected female newborns are profoundly virilized (Prader score of 4/5), and both genders display significantly advanced bone ages and are oftentimes hypertensive. We find that 11-deoxycortisol, not frequently measured, is the most robust biochemical marker for diagnosing 11β-hydroxylase deficiency. Finally, computational modeling of 25 missense mutations of CYP11B1 revealed that specific modifications in the heme-binding (R374W and R448C) or substrate-binding (W116C) site of 11β-hydroxylase, or alterations in its stability (L299P and G267S), may predict severe disease. Thus, we report clinical, genetic, hormonal, and structural effects of CYP11B1 gene mutations in the largest international cohort of 108 patients with steroid 11β-hydroxylase deficiency CAH.Keywords
Funding Information
- HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (DK80459)
- HHS | NIH | National Institute on Aging (AG40132)
- HHS | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR06592)
- HHS | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR06066)
This publication has 39 references indexed in Scilit:
- GROMACS 4.5: a high-throughput and highly parallel open source molecular simulation toolkitBioinformatics, 2013
- Structure and Dynamics of the Membrane-Bound Cytochrome P450 2C9PLoS Computational Biology, 2011
- Steroid 11-beta hydroxylase deficiency caused by compound heterozygosity for a novel mutation in intron 7 (IVS 7 DS+4A to G) in one CYP11B1 allele and R448H in exon 8 in the otherEuropean Journal of Pediatrics, 2009
- Consanguinity and reproductive health among ArabsReproductive Health, 2009
- ProSA-web: interactive web service for the recognition of errors in three-dimensional structures of proteinsNucleic Acids Research, 2007
- Update on the Prenatal Diagnosis and Treatment of Congenital Adrenal Hyperplasia due to 11β-Hydroxylase DeficiencyJournal of Pediatric Endocrinology and Metabolism, 2005
- Consanguineous marriages in the province of Antalya, TurkeyAnnales de Genetique, 2004
- Prenatal Diagnosis and Treatment of 11 -Hydroxylase Deficiency Congenital Adrenal Hyperplasia Resulting in Normal Female GenitaliaJournal of Clinical Endocrinology & Metabolism, 1999
- Congenital adrenal hyperplasia in Turkey: a review of 273 patientsActa Paediatrica, 1997
- AQUA and PROCHECK-NMR: Programs for checking the quality of protein structures solved by NMRJournal of Biomolecular NMR, 1996