Ethnic-specific distribution of mutations in 716 patients with congenital adrenal hyperplasia owing to 21-hydroxylase deficiency

Wilson, Robert; Nimkarn, Saroj; Dumić, Miroslav; Obeid, Jihad S.; Azar, Maryam Razzaghy; Najmabadi, Hossein; Saffari, Fatemeh; New, Maria I.

doi:10.1016/j.ymgme.2006.12.005

Cited by 118 publications

(126 citation statements)

References 54 publications

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“…60 In the Yupik speaking Eskimos of Western Alaska and Iranians, the IVS2-13A/C>G (c.293-13A/ C>G) mutation predominates. 59 One study found at least half of all patients with 21-OHD in Finland were due to 3 most common founder mutation-haplotypes, and only one-sixth of the haplotypes represented single cases. 61 Of the chimeras, CH-7 was first identified in a Czech population and represents the most frequent allele.…”

Section: Population Genetics and Ethnic Diversity Of Cyp21a2 Genotypesmentioning

confidence: 99%

“…3 Certain ethnic groups have a predilection to certain genotypes (Table 3), 9,23,24,52-58 which may have resulted from an ancient founder effect, unequal crossing over during meiosis or gene conversion of point mutations in the pseudogene. 59 In the United States, the allele frequency of the most common mutations might vary considerably between different ethnicities. For instance, the exon 7 p.V281L (c.1685G>T) mutation associated with NCCAH is very frequent in the Ashkenazi Jewish (AJ) population of New York (estimated in one study to be 1 in 27, with 1 in 3 being heterozygous), which has not been observed in the Asian and Native American populations.…”

Section: Population Genetics and Ethnic Diversity Of Cyp21a2 Genotypesmentioning

confidence: 99%

“…Among compound heterozygotes in the AJ population, the prevalent mutations are large deletion/p.V281L (c.1685G>T) and IVS2-13A/C>G (c.293-13A/C>G)/p.V281L (c.1685G>T). 59 CAH is rare in Asian, African American, and East Indian populations of New York, while a large gene deletion is observed in Native Americans. 6 Conversely, the IVS2-13A/C>G genotype and p.V281L are more prevalent in the Middle Eastern population; the common p.Q318X mutation is by far the most frequently found in the Tunisian population.…”

Section: Population Genetics and Ethnic Diversity Of Cyp21a2 Genotypesmentioning

confidence: 99%

“…60 In the Yupik speaking Eskimos of Western Alaska and Iranians, the IVS2-13A/C>G (c.293-13A/ C>G) mutation predominates. 59 One study found at least half of all patients with 21-OHD in …”

mentioning

confidence: 99%

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Genetics of Congenital Adrenal Hyperplasia

Hannah‐Shmouni

Chen²,

Merke

2017

Endocrinology and Metabolism Clinics of North America

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Section: Population Genetics and Ethnic Diversity Of Cyp21a2 Genotypesmentioning

confidence: 99%

Section: Population Genetics and Ethnic Diversity Of Cyp21a2 Genotypesmentioning

confidence: 99%

Section: Population Genetics and Ethnic Diversity Of Cyp21a2 Genotypesmentioning

confidence: 99%

“…60 In the Yupik speaking Eskimos of Western Alaska and Iranians, the IVS2-13A/C>G (c.293-13A/ C>G) mutation predominates. 59 One study found at least half of all patients with 21-OHD in …”

mentioning

confidence: 99%

See 2 more Smart Citations

Genetics of Congenital Adrenal Hyperplasia

Hannah‐Shmouni

Chen²,

Merke

2017

Endocrinology and Metabolism Clinics of North America

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“…From our own work over the past three decades, and from the work of others, over 100 CYP21A2 mutations have been cataloged. In most cases, genotypes and phenotypes are correlated (5). However, in rare instances, genotypephenotype discordance has been reported (6).…”

mentioning

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.

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115

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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Molecular Genetics of 21‐Hydroxylase Deficiency

Parajes

Krone

2014

Encyclopedia of Life Sciences

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Steroid 21‐hydroxylase deficiency (21OHD) accounts for approximately 95% of cases of congenital adrenal hyperplasia, one of the most common inherited metabolic disorders. It can be clinically classified into classic and nonclassic 21OHD. Classic 21OHD is associated with glucocorticoid deficiency and, in 46,XX patients, with disorder of sex development. Mineralocorticoid synthesis may also be significantly impaired in two‐thirds of patients, leading to life‐threatening salt‐wasting (SW) crises. Nonclassic 21OHD is milder and presents mainly with hyperandrogenism. 21OHD is caused by mutations in the CYP21A2 gene. The vast majority of CYP21A2 mutations are a result of unequal crossing overs and gene conversions with its highly homologous pseudogene, CYP21A1P . Molecular genetic analysis is challenging and requires the combination of different methods to detect gene deletions, chimeric genes, gene duplications and point mutations. An overall good genotype–phenotype correlation exists for the SW phenotype. Therefore, molecular diagnosis of 21OHD complements clinical diagnosis and allows for clinical and genetic counselling. Key Concepts: Steroid 21‐hydroxylase deficiency (21OHD) is an autosomal recessive disorder caused by mutations in the CYP21A2 gene and represents the most common form of congenital adrenal hyperplasia. A good genotype–phenotype correlation exists for the mineralocorticoid deficiency phenotype. Although a trend exists, the severity of 46,XX disorder of sex development as well as of other hyperandrogenic signs and symptoms correlates less strongly with the CYP21A2 genotype. Common pseudogene‐derived mutations account for the majority of 21OHD disease‐causing alleles; these include gene deletions, chimeric genes, seven single point mutations, an 8 base‐pair deletion and a cluster of three point mutations. Molecular genetic analysis of the CYP21A2 gene is challenging due to the high‐sequence homology with its pseudogene ( CYP21A1P ), the high rate of large rearrangements with different break points, and the presence of complex alleles carrying various mutations. Some less common mutations are highly prevalent in specific populations due to founder effects. These should be considered in the genetic diagnosis of 21OHD when only screening for otherwise common CYP21A2 mutations. CYP21A2 gene duplications should be considered in carriers of the p.Gln318X mutation to provide the correct molecular genetic diagnosis. Molecular genetic diagnosis is essential to provide the correct diagnosis and allows for appropriate clinical and genetic counselling.

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Ethnic-specific distribution of mutations in 716 patients with congenital adrenal hyperplasia owing to 21-hydroxylase deficiency

Cited by 118 publications

References 54 publications

Genetics of Congenital Adrenal Hyperplasia

Genetics of Congenital Adrenal Hyperplasia

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

Molecular Genetics of 21‐Hydroxylase Deficiency

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