Steroid 21-hydroxylase deficiency: Mutational spectrum in Denmark, three novel mutations, and in vitro expression analysis

Ohlsson, Gita; Müller, Jørn; Skakkebæk, Niels E.; Schwartz, Marianne

doi:10.1002/(sici)1098-1004(1999)13:6<482::aid-humu8>3.0.co;2-0

Cited by 27 publications

(12 citation statements)

References 20 publications

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“…Except for two Danish cases, the cases were intron 2 splicing mutations and consistent with the hotspot for unequal crossover in the CYP21 gene (Collier et al, 1993;Tajima et al, 1993;Levo and Partanen, 2001;Sinnott et al, 1989). The de novo mutation of I172N was found in the two Danish cases, which could be founder-specific (Ohlsson et al, 1999). In this report, the parental samples from 37 different families were available for genotyping.…”

Section: De Novo Mutations In the Cyp21 Gene 123mentioning

confidence: 52%

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The Implication of De Novo 21-Hydroxylase Mutation in Clinical and Prenatal Molecular Diagnoses

et al. 2005

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We studied 37 unrelated families with a history of 21-hydroxylase deficiency (CYP21D) for eight common mutations and gene deletions in the 21-hydroxylase (CYP21) gene. We found de novo mutations in the CYP21 gene in two CYP21D patients. Analysis for eight common mutations in the 21-hydroxylase gene as well as large gene deletions was accomplished using polymerase chain reaction (PCR) followed by amplified created restriction site (ACRS) or restriction fragment length polymorphism (RFLP) and Southern blot followed by hybridization to a CYP21-specific probe. Linkage analysis was performed using microsatellite markers flanking the CYP21 gene. Ten short tandem repeat (STR) markers were used to confirm parentage in the two de novo mutation cases. In two prenatal diagnosis cases, an intron 2-13A/C>G mutation was identified in the proband, but not in the fetus, although the proband and fetus had identical linkage markers. Subsequently, the mutation was confirmed to be absent in the parents' genome and misparentage was ruled out. Our findings are consistent with previous studies showing a de novo mutation frequency of approximately 1.0-1.5% in the CYP21 gene. This new mutation rate is high relative to the rate of approximately one in one million for other autosomal recessive disorders. Thus, the de novo mutation rate in the CYP21 gene is not negligible. It must be considered and discussed in prenatal diagnosis and genetic counseling for this relatively common inherited disorder.

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Section: De Novo Mutations In the Cyp21 Gene 123mentioning

confidence: 52%

“…F, the fetus. not et al, 1989Heitmancik et al, 1992;Collier et al, 1993;Tajima et al, 1993;Levo and Partanen, 2001;Ohlsson et al, 1999). All of them reported that de novo mutations occurred on the maternally inherited chromosomes.…”

Section: De Novo Mutations In the Cyp21 Gene 123mentioning

confidence: 99%

The Implication of De Novo 21-Hydroxylase Mutation in Clinical and Prenatal Molecular Diagnoses

et al. 2005

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“…Two additional salt-wasting mutations in the N-terminal region, G65E (40) and G91V (41), that reduce P450 21A2 activity to Ͻ1%, 6 can now be readily interpreted in light of the human P450 21A2 crystal structure. Gly-65 maps to a hydrophobic patch, and mutation to a glutamate would disrupt hydrophobic interactions and result in a direct clash with the side chain of Val-212 (Fig.…”

Section: Discussionmentioning

confidence: 99%

Human Cytochrome P450 21A2, the Major Steroid 21-Hydroxylase

Pallan

Wang

Lei

et al. 2015

Journal of Biological Chemistry

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Background: P450 21A2 catalyzes 21-hydroxylation of both progesterone and 17␣-hydroxyprogesterone, an important step in adrenal steroidogenesis. Results: A crystal structure of human P450 21A2 with progesterone can explain many functional variants. Conclusion: High kinetic deuterium isotope effects show the importance of a closely spaced site for C21 hydrogen abstraction. Significance: The structure provides insight into enzyme deficiencies in congenital adrenal hyperplasia.

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“…We show that this in silico approach can predict the extent of loss of function of the steroidogenic CYP21A2 enzyme. With certain mutations, varying degrees of loss of function have been confirmed biochemically by overexpressing the mutated enzyme in vitro (27)(28)(29)(30)(31)(32), whereas, in other cases, the extent to which the enzyme is disrupted remains unknown.…”

Section: Discussionmentioning

confidence: 99%

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

Haider

Islam

D’Atri

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

114

130

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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, saltbridge 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.structure-phenotype correlation | molecular modeling | CYP21A2 structural analysis

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Steroid 21-hydroxylase deficiency: Mutational spectrum in Denmark, three novel mutations, and in vitro expression analysis

Cited by 27 publications

References 20 publications

The Implication of De Novo 21-Hydroxylase Mutation in Clinical and Prenatal Molecular Diagnoses

The Implication of De Novo 21-Hydroxylase Mutation in Clinical and Prenatal Molecular Diagnoses

Human Cytochrome P450 21A2, the Major Steroid 21-Hydroxylase

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

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