Abstract
Congenital adrenal hyperplasia due to 21-hydroxylase deficiency accounts for 90–95% of CAH cases. In this work we performed an extensive survey of mutations and SNPs modifying the coding sequence of the CYP21A2 gene. Using bioinformatic tools and two plausible CYP21A2 structures as templates, we initially classified all known mutants (n = 343) according to their putative functional impacts, which were either reported in the literature or inferred from structural models. We then performed a detailed analysis on the subset of mutations believed to exclusively impact protein stability. For those mutants, the predicted stability was calculated and correlated with the variant’s expected activity. A high concordance was obtained when comparing our predictions with available in vitro residual activities and/or the patient’s phenotype. The predicted stability and derived activity of all reported mutations and SNPs lacking functional assays (n = 108) were assessed. As expected, most of the SNPs (52/76) showed no biological implications. Moreover, this approach was applied to evaluate the putative synergy that could emerge when two mutations occurred in cis. In addition, we propose a putative pathogenic effect of five novel mutations, p.L107Q, p.L122R, p.R132H, p.P335L and p.H466fs, found in 21-hydroxylase deficient patients of our cohort.
Highlights
Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (OMIM 201910) represents 90–95% of all CAH cases[1,2,3]
There are 57 genes and more than 59 pseudogenes grouped in 18 families and 43 subfamilies, all with a high sequence identity9. 21-hydroxylase displays microsomal localization[10] and, like other microsomal P450s, this enzyme accepts electrons provided by a NADPH-dependent P450 oxidoreductase (POR), reducing molecular oxygen and hydrolyzing substrates
With the aim of predicting the effect of uncharacterized mutations, we initially performed an extensive survey of mutations and single nucleotide polymorphisms (SNPs) modifying the coding sequence of the gene (n = 343)
Summary
Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (OMIM 201910) represents 90–95% of all CAH cases[1,2,3] This autosomal recessive disorder, which is the most frequent inborn error of metabolism, has a broad spectrum of clinical forms, ranging from severe or classical, to mild late onset or non-classical (NC). Due to the high degree of sequence identity between the gene and its pseudogene, most of the disease-causing mutations described in 21-hydroxylase deficiency are likely to be the consequence of non-homologous recombination or gene conversion events[6,7]. 21-hydroxylase displays microsomal localization[10] and, like other microsomal P450s, this enzyme accepts electrons provided by a NADPH-dependent P450 oxidoreductase (POR), reducing molecular oxygen and hydrolyzing substrates. This enzyme has 494–495 aminoacids with a molecular weight of 52 kDa11,12
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