Abstract
Congenital adrenal hyperplasia (CAH), resulting from mutations inCYP11B1, 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 ofCYP11B1revealed 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 ofCYP11B1gene mutations in the largest international cohort of 108 patients with steroid 11β-hydroxylase deficiency CAH.
Funder
HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases
HHS | NIH | National Institute on Aging
HHS | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases
Publisher
Proceedings of the National Academy of Sciences
Cited by
102 articles.
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