Structure-phenotype correlations of human CYP21A2 mutations in congenital adrenal hyperplasia

Shozeb Haider, Barira Islam, Valentina D'Atri, Miriam Sgobba, Chetan Poojari, Li Sun, Tony Yuen, Mone Zaidi, Maria I New

Research output: Contribution to journalArticle

59 Citations (Scopus)

Abstract

Mutations in the cytochrome p450 (CYP)21A2 gene, which encodes the enzyme steroid 21-hydroxylase, cause the majority of cases in congenital adrenal hyperplasia, an autosomal recessive disorder. To date, more than 100 CYP21A2 mutations have been reported. These mutations can be associated either with severe salt-wasting or simple virilizing phenotypes or with milder nonclassical phenotypes. Not all CYP21A2 mutations have, however, been characterized biochemically, and the clinical consequences of these mutations remain unknown. Using the crystal structure of its bovine homolog as a template, we have constructed a humanized model of CYP21A2 to provide comprehensive structural explanations for the clinical manifestations caused by each of the known disease-causing missense mutations in CYP21A2. Mutations that affect membrane anchoring, disrupt heme and/or substrate binding, or impair stability of CYP21A2 cause complete loss of function and salt-wasting disease. In contrast, mutations altering the transmembrane region or conserved hydrophobic patches cause up to a 98% reduction in enzyme activity and simple virilizing disease. Mild nonclassical disease can result from interference in oxidoreductase interactions, salt-bridge and hydrogen-bonding networks, and nonconserved hydrophobic clusters. A simple in silico evaluation of previously uncharacterized gene mutations could, thus, potentially help predict the often diverse phenotypes of a monogenic disorder.

LanguageEnglish
Pages2605-2610
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number7
DOIs
Publication statusPublished - 12 Feb 2013
Externally publishedYes

Fingerprint

Congenital Adrenal Hyperplasia
Phenotype
Mutation
Salts
Wasting Syndrome
Steroid 21-Hydroxylase
Missense Mutation
Enzymes
Hydrogen Bonding
Heme
Computer Simulation
Cytochrome P-450 Enzyme System
Genes
Oxidoreductases
Membranes

Cite this

Haider, Shozeb ; Islam, Barira ; D'Atri, Valentina ; Sgobba, Miriam ; Poojari, Chetan ; Sun, Li ; Yuen, Tony ; Zaidi, Mone ; New, Maria I. / Structure-phenotype correlations of human CYP21A2 mutations in congenital adrenal hyperplasia. In: Proceedings of the National Academy of Sciences of the United States of America. 2013 ; Vol. 110, No. 7. pp. 2605-2610.
@article{99d9e891fd7c4a97aae76fb285644667,
title = "Structure-phenotype correlations of human CYP21A2 mutations in congenital adrenal hyperplasia",
abstract = "Mutations in the cytochrome p450 (CYP)21A2 gene, which encodes the enzyme steroid 21-hydroxylase, cause the majority of cases in congenital adrenal hyperplasia, an autosomal recessive disorder. To date, more than 100 CYP21A2 mutations have been reported. These mutations can be associated either with severe salt-wasting or simple virilizing phenotypes or with milder nonclassical phenotypes. Not all CYP21A2 mutations have, however, been characterized biochemically, and the clinical consequences of these mutations remain unknown. Using the crystal structure of its bovine homolog as a template, we have constructed a humanized model of CYP21A2 to provide comprehensive structural explanations for the clinical manifestations caused by each of the known disease-causing missense mutations in CYP21A2. Mutations that affect membrane anchoring, disrupt heme and/or substrate binding, or impair stability of CYP21A2 cause complete loss of function and salt-wasting disease. In contrast, mutations altering the transmembrane region or conserved hydrophobic patches cause up to a 98{\%} reduction in enzyme activity and simple virilizing disease. Mild nonclassical disease can result from interference in oxidoreductase interactions, salt-bridge and hydrogen-bonding networks, and nonconserved hydrophobic clusters. A simple in silico evaluation of previously uncharacterized gene mutations could, thus, potentially help predict the often diverse phenotypes of a monogenic disorder.",
keywords = "Adrenal Hyperplasia, Congenital/genetics, Animals, Cattle, Cell Membrane/metabolism, Computational Biology, Heme/metabolism, Humans, Hydrogen Bonding, Models, Molecular, Molecular Dynamics Simulation, Mutation, Missense/genetics, Phenotype, Protein Binding, Protein Conformation, Steroid 21-Hydroxylase/genetics",
author = "Shozeb Haider and Barira Islam and Valentina D'Atri and Miriam Sgobba and Chetan Poojari and Li Sun and Tony Yuen and Mone Zaidi and New, {Maria I}",
year = "2013",
month = "2",
day = "12",
doi = "10.1073/pnas.1221133110",
language = "English",
volume = "110",
pages = "2605--2610",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "7",

}

Structure-phenotype correlations of human CYP21A2 mutations in congenital adrenal hyperplasia. / Haider, Shozeb; Islam, Barira; D'Atri, Valentina; Sgobba, Miriam; Poojari, Chetan; Sun, Li; Yuen, Tony; Zaidi, Mone; New, Maria I.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 110, No. 7, 12.02.2013, p. 2605-2610.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Structure-phenotype correlations of human CYP21A2 mutations in congenital adrenal hyperplasia

AU - Haider, Shozeb

AU - Islam, Barira

AU - D'Atri, Valentina

AU - Sgobba, Miriam

AU - Poojari, Chetan

AU - Sun, Li

AU - Yuen, Tony

AU - Zaidi, Mone

AU - New, Maria I

PY - 2013/2/12

Y1 - 2013/2/12

N2 - Mutations in the cytochrome p450 (CYP)21A2 gene, which encodes the enzyme steroid 21-hydroxylase, cause the majority of cases in congenital adrenal hyperplasia, an autosomal recessive disorder. To date, more than 100 CYP21A2 mutations have been reported. These mutations can be associated either with severe salt-wasting or simple virilizing phenotypes or with milder nonclassical phenotypes. Not all CYP21A2 mutations have, however, been characterized biochemically, and the clinical consequences of these mutations remain unknown. Using the crystal structure of its bovine homolog as a template, we have constructed a humanized model of CYP21A2 to provide comprehensive structural explanations for the clinical manifestations caused by each of the known disease-causing missense mutations in CYP21A2. Mutations that affect membrane anchoring, disrupt heme and/or substrate binding, or impair stability of CYP21A2 cause complete loss of function and salt-wasting disease. In contrast, mutations altering the transmembrane region or conserved hydrophobic patches cause up to a 98% reduction in enzyme activity and simple virilizing disease. Mild nonclassical disease can result from interference in oxidoreductase interactions, salt-bridge and hydrogen-bonding networks, and nonconserved hydrophobic clusters. A simple in silico evaluation of previously uncharacterized gene mutations could, thus, potentially help predict the often diverse phenotypes of a monogenic disorder.

AB - Mutations in the cytochrome p450 (CYP)21A2 gene, which encodes the enzyme steroid 21-hydroxylase, cause the majority of cases in congenital adrenal hyperplasia, an autosomal recessive disorder. To date, more than 100 CYP21A2 mutations have been reported. These mutations can be associated either with severe salt-wasting or simple virilizing phenotypes or with milder nonclassical phenotypes. Not all CYP21A2 mutations have, however, been characterized biochemically, and the clinical consequences of these mutations remain unknown. Using the crystal structure of its bovine homolog as a template, we have constructed a humanized model of CYP21A2 to provide comprehensive structural explanations for the clinical manifestations caused by each of the known disease-causing missense mutations in CYP21A2. Mutations that affect membrane anchoring, disrupt heme and/or substrate binding, or impair stability of CYP21A2 cause complete loss of function and salt-wasting disease. In contrast, mutations altering the transmembrane region or conserved hydrophobic patches cause up to a 98% reduction in enzyme activity and simple virilizing disease. Mild nonclassical disease can result from interference in oxidoreductase interactions, salt-bridge and hydrogen-bonding networks, and nonconserved hydrophobic clusters. A simple in silico evaluation of previously uncharacterized gene mutations could, thus, potentially help predict the often diverse phenotypes of a monogenic disorder.

KW - Adrenal Hyperplasia, Congenital/genetics

KW - Animals

KW - Cattle

KW - Cell Membrane/metabolism

KW - Computational Biology

KW - Heme/metabolism

KW - Humans

KW - Hydrogen Bonding

KW - Models, Molecular

KW - Molecular Dynamics Simulation

KW - Mutation, Missense/genetics

KW - Phenotype

KW - Protein Binding

KW - Protein Conformation

KW - Steroid 21-Hydroxylase/genetics

U2 - 10.1073/pnas.1221133110

DO - 10.1073/pnas.1221133110

M3 - Article

VL - 110

SP - 2605

EP - 2610

JO - Proceedings of the National Academy of Sciences of the United States of America

T2 - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 7

ER -