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Clinical, genetic, and structural basis of congenital adrenal hyperplasia due to 11?-hydroxylase deficiency.


ABSTRACT: Congenital adrenal hyperplasia (CAH), resulting from mutations in CYP11B1, a gene encoding 11?-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 11?-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 11?-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 11?-hydroxylase deficiency CAH.

SUBMITTER: Khattab A 

PROVIDER: S-EPMC5347606 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Clinical, genetic, and structural basis of congenital adrenal hyperplasia due to 11β-hydroxylase deficiency.

Khattab Ahmed A   Haider Shozeb S   Kumar Ameet A   Dhawan Samarth S   Alam Dauood D   Romero Raquel R   Burns James J   Li Di D   Estatico Jessica J   Rahi Simran S   Fatima Saleel S   Alzahrani Ali A   Hafez Mona M   Musa Noha N   Razzghy Azar Maryam M   Khaloul Najoua N   Gribaa Moez M   Saad Ali A   Charfeddine Ilhem Ben IB   Bilharinho de Mendonça Berenice B   Belgorosky Alicia A   Dumic Katja K   Dumic Miroslav M   Aisenberg Javier J   Kandemir Nurgun N   Alikasifoglu Ayfer A   Ozon Alev A   Gonc Nazli N   Cheng Tina T   Kuhnle-Krahl Ursula U   Cappa Marco M   Holterhus Paul-Martin PM   Nour Munier A MA   Pacaud Daniele D   Holtzman Assaf A   Li Sun S   Zaidi Mone M   Yuen Tony T   New Maria I MI  

Proceedings of the National Academy of Sciences of the United States of America 20170222 10


Congenital adrenal hyperplasia (CAH), resulting from mutations in <i>CYP11B1</i>, 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 disp  ...[more]

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