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Novel non-classic CYP21A2 variants, including combined alleles, identified in patients with congenital adrenal hyperplasia
Karolinska Univ Hosp, Karolinska Inst, Dept Womens & Childrens Hlth, Pediat Endocrinol Unit Q2 08, Stockholm, Sweden.
Karolinska Univ Hosp, Karolinska Inst, Dept Womens & Childrens Hlth, Pediat Endocrinol Unit Q2 08, Stockholm, Sweden; Univ Estadual Campinas, Ctr Biol Mol & Engn Genet, Lab Genet Mol Humana, Campinas, SP, Brazil.
Univ Estadual Campinas, Ctr Biol Mol & Engn Genet, Lab Genet Mol Humana, Campinas, SP, Brazil.
Univ Estadual Campinas, Fac Ciencias Med, Dept Pediat, Campinas, SP, Brazil.
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2019 (English)In: Clinical Biochemistry, ISSN 0009-9120, E-ISSN 1873-2933, Vol. 73, p. 50-56Article in journal (Refereed) Published
Abstract [en]

Objective: Congenital adrenal hyperplasia (CAH) is an inborn error of metabolism and a common disorder of sex development where >90% of all cases are due to 21-hydroxylase deficiency. Novel and rare pathogenic variants account for 5% of all clinical cases. Here, we sought to investigate the functional and structural effects of four novel (p.Val358Ile, p.Arg369Gln, p.Asp377Tyr, and p.Leu461Pro) and three combinations of CYP21A2 variants (i.e. one allele containing two variants p.[Ile172Asn;Val358Ile], p.[Val281Leu;Arg369Gln], or p.[Asp377Tyr;Leu461Pro]) identified in patients with CAH.

Methods: All variants were reconstructed by in vitro site-directed mutagenesis, the proteins were transiently expressed in COS-1 cells and enzyme activities directed toward the two natural substrates (17-hydroxyprogesterone and progesterone) were determined. In parallel, in silico prediction of the pathogenicity of the variants based on the human CYP21 X-ray structure was performed.

Results: The novel variants, p.Val358Ile, p.Arg369Gln, p.Asp377Tyr, and p.Leu461Pro exhibited residual enzymatic activities within the range of non-classic (NC) CAH variants (40–82%). An additive effect on the reduction of enzymatic activity (1–17%) was observed when two variants were expressed together, as identified in several patients, resulting in either NC or more severe phenotypes. In silico predictions were in line with the in vitro data except for p.Leu461Pro.

Conclusions: Altogether, the combination of clinical data, in silico prediction, and data from in vitro studies are important for establishing a correct genotype and phenotype correlation in patients with CAH.

 

Place, publisher, year, edition, pages
2019. Vol. 73, p. 50-56
Keywords [en]
21-hydroxylase, Functional studies, Congenital adrenal hyperplasia, Synergistic effects
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-397413DOI: 10.1016/j.clinbiochem.2019.07.009ISI: 000492745500007PubMedID: 31344365OAI: oai:DiVA.org:uu-397413DiVA, id: diva2:1371543
Funder
Sven Jerring FoundationStockholm County CouncilMarianne and Marcus Wallenberg FoundationAvailable from: 2019-11-20 Created: 2019-11-20 Last updated: 2019-11-20Bibliographically approved

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