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

Khattab, A; Haider, S; Kumar, A; Dhawan, S; Alam, D; Romero, R; Burns, J; ... New, MI; + view all (2017) Clinical, genetic, and structural basis of congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency. Proceedings of the National Academy of Sciences of the United States of America , 114 (10) E1933-E1940. 10.1073/pnas.1621082114/-/DCSupplemental. Green open access

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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.

Type: Article
Title: Clinical, genetic, and structural basis of congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency
Open access status: An open access version is available from UCL Discovery
DOI: 10.1073/pnas.1621082114/-/DCSupplemental
Publisher version: http://doi.org/10.1073/pnas.1621082114/-/DCSupplem...
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharma and Bio Chemistry
URI: https://discovery.ucl.ac.uk/id/eprint/1547227
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