Inhibition of CYP21A2 Enzyme Activity Caused by Novel Missense Mutations Identified in Brazilian and Scandinavian Patients

Soardi, Fernanda Caroline; Barbaro, Michela; Lau, Ivy F.; Lemos-Marini, Sofia Helena Valente de; Baptista, Mónica; Guerra, Gil; Wedell, Anna; Lajić, Svetlana; Mello, Maricilda Palandi de

doi:10.1210/jc.2007-2594

Cited by 61 publications

(43 citation statements)

References 21 publications

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“…Of these, we have routinely studied nine common allelic mutations, the frequency of which is shown in Table 1. The frequency values in our patient cohort are ranked from most to least frequent (1)(2)(3)(4)(5)(6)(7)(8)(9) and are compared against rankings reported in four previous studies (15,16,21,22). Overall, the rankings were similar, especially with respect to the high frequency of deletion and g.655A/C>G (I2G) mutations and the low frequency of P30L, exon 3 8-bp deletion (E3Δ8bp), and exon 6 I236N, V237E, and M239K cluster (E6) mutations (Table 1).…”

Section: Resultsmentioning

confidence: 99%

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Genotype–phenotype correlation in 1,507 families with congenital adrenal hyperplasia owing to 21-hydroxylase deficiency

New¹,

Abraham²,

Gonzalez³

et al. 2013

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

303

299

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Over the last two decades, we have extensively studied the genetics of congenital adrenal hyperplasia caused by 21-hydroxylase deficiency (CAH) and have performed 8,290 DNA analyses of the CYP21A2 gene on members of 4,857 families at risk for CAHthe largest cohort of CAH patients reported to date. Of the families studied, 1,507 had at least one member affected with one of three known forms of CAH, namely salt wasting, simple virilizing, or nonclassical CAH. Here, we report the genotype and phenotype of each affected patient, as well as the ethnic group and country of origin for each patient. We showed that 21 of 45 genotypes yielded a phenotypic correlation in our patient cohort. In particular, contrary to what is generally reported in the literature, we found that certain mutations, for example, the P30L, I2G, and I172N mutations, yielded different CAH phenotypes. In salt wasting and nonclassical CAH, a phenotype can be attributed to a genotype; however, in simple virilizing CAH, we observe wide phenotypic variability, particularly with the exon 4 I172N mutation. Finally, there was a high frequency of homozygous I2G and V281L mutations in Middle Eastern and Ashkenazi Jewish populations, respectively. By identifying the predominant phenotype for a given genotype, these findings should assist physicians in prenatal diagnosis and genetic counseling of parents who are at risk for having a child with CAH.pseudogene-derived mutations | genotype-phenotype association T he most common cause of congenital adrenal hyperplasia (CAH) is 21-hydroxylase deficiency (1). Phenotypically, CAH can be divided into classical and nonclassical (NC) forms, with the classical form presenting as salt-wasting (SW) or simple-virilizing (SV) CAH (1), both of which can result in genital ambiguity in the affected female. Mutations in the CYP21A2 gene cause varying degrees of loss of 21-hydroxylase activity, resulting in different severities. In vitro studies performed on a relatively limited number of mutations have confirmed a correlation between disease severity and the degree of functional loss of 21-hydroxylase. Mutations resulting in complete inactivation of 21-hydroxylase activity are associated with the SW phenotype. Those that reduce enzyme activity to ∼2% cause the SV phenotype, whereas those that reduce activity to between 10% and 75% result in the mild NC phenotype (2-12).We recently used computational modeling to correlate disease severity with 113 known mutations on the basis of the extent to which the enzyme is disrupted in silico (13). By humanizing the crystal structure of bovine CYP21A2, we found that mutations that affect critical enzyme functions, such as membrane anchoring, heme binding, and substrate binding, or alter enzyme stability result in a complete loss of functionality and SW disease. In contrast, mutations that affect the transmembrane region or conserved hydrophobic patches result in up to a 98% reduction in enzyme activity and SV disease. Mild NC disease arises from interference in oxidoreductase interactions,...

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Section: Resultsmentioning

confidence: 99%

“…Mutations resulting in complete inactivation of 21-hydroxylase activity are associated with the SW phenotype. Those that reduce enzyme activity to ∼2% cause the SV phenotype, whereas those that reduce activity to between 10% and 75% result in the mild NC phenotype (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12).…”

mentioning

confidence: 99%

Genotype–phenotype correlation in 1,507 families with congenital adrenal hyperplasia owing to 21-hydroxylase deficiency

New¹,

Abraham²,

Gonzalez³

et al. 2013

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

303

299

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“…None of the patients used hypoglycemic or hypolipidemic drugs. Diagnosis of 21OHD CAH was determined during the first year of life by clinical features and hormonal measurements, and it was confirmed later on by molecular genetic testing (23,24).…”

Section: Methodsmentioning

confidence: 99%

Metabolic evaluation of young women with congenital adrenal hyperplasia

Schnaider-Rezek

Lemos-Marini

Baptista

et al. 2011

Arq Bras Endocrinol Metab

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Objective: To evaluate insulin resistance and lipid profile in women with congenital adrenal hyperplasia (CAH) caused by classical 21-hydroxylase deficiency (21OHD), and their association with body mass index (BMI) and corticosteroid dosage. Subjects and methods: We assessed BMI, waist circumference, current glucocorticoid dosage, glucose, insulin and lipid profile in eighteen young women (mean ± SD, 19.3 ± 3.0 years) with 21OHD CAH. Results: BMI was normal in 12 patients, 5 of them were overweight, and 1 was obese. Waist circumference was high in 7 patients. Fasting insulin and HOMA-IR were elevated in seven and eight patients, respectively. Total cholesterol and triglycerides were high in only two patients, and HDL-cholesterol was low in four. Insulin resistance was not associated with BMI, waist circumference or glucocorticoid dose. Conclusions: Young women with 21OHD CAH had infrequent dyslipidemia, but had a higher prevalence of insulin resistance and central obesity, that were independent of BMI or corticosteroid dosage. Arq Bras Endocrinol Metab. 2011;55(8):646-52

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“…In addition, functional and expression studies have been used in in vitro assays to search for novel mutations (11)(12)(13)(14). The identification of large chromosomal rearrangements and gene dosage analyses have mostly been performed with Southern blot techniques (15)(16)(17), quantitative real-time PCR methods (18 -20 ), and, recently, multiplex ligation-dependent probe amplification (MLPA) (21 ).…”

confidence: 99%

Sequence Analysis of CYP21A1P in a German Population to Aid in the Molecular Biological Diagnosis of Congenital Adrenal Hyperplasia

et al. 2011

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BACKGROUND The high homology between the CYP21A2 (cytochrome P450, family 21, subfamily A, polypeptide 2) and CYP21A1P (cytochrome P450, family 21, subfamily A, polypeptide 1 pseudogene) genes is the major obstacle to risk-free genetic diagnosis of congenital adrenal hyperplasia, especially regarding the quantification of gene dosage. Because of the lack of a comprehensive study providing useful information about the detailed genetic structure of CYP21A1P, we used a large data set to analyze and characterize this pseudogene. METHODS We amplified and directly sequenced the CYP21A1P and CYP21A2 genes of 200 unrelated individuals. The resulting sequence data were aligned against the manually curated transcript ENST0000448314 from Havana/Vega matching to the genebuild ENSG00000198457; all differences were documented. Copy number was measured by multiplex ligation-dependent probe amplification when necessary. RESULTS We found that 40 potentially variable positions in CYP21A2 were conserved in CYP21A1P in all study participants. In addition, we detected 14 CYP21A1P variants that were not previously reported in either CYP21A2 or CYP21A1P. Unlike CYP21A2, CYP21A1P possessed certain mutation haplotypes. CONCLUSIONS The genetic structure of CYP21A1P and the potential risks of false conclusions it may introduce are essential considerations in designing a PCR-based diagnosis procedure for congenital adrenal hyperplasia.

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Inhibition of CYP21A2 Enzyme Activity Caused by Novel Missense Mutations Identified in Brazilian and Scandinavian Patients

Cited by 61 publications

References 21 publications

Genotype–phenotype correlation in 1,507 families with congenital adrenal hyperplasia owing to 21-hydroxylase deficiency

Genotype–phenotype correlation in 1,507 families with congenital adrenal hyperplasia owing to 21-hydroxylase deficiency

Metabolic evaluation of young women with congenital adrenal hyperplasia

Sequence Analysis of CYP21A1P in a German Population to Aid in the Molecular Biological Diagnosis of Congenital Adrenal Hyperplasia

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