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http://purl.uniprot.org/citations/31344365http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/31344365http://www.w3.org/2000/01/rdf-schema#comment"

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."xsd:string
http://purl.uniprot.org/citations/31344365http://purl.org/dc/terms/identifier"doi:10.1016/j.clinbiochem.2019.07.009"xsd:string
http://purl.uniprot.org/citations/31344365http://purl.uniprot.org/core/author"Persson B."xsd:string
http://purl.uniprot.org/citations/31344365http://purl.uniprot.org/core/author"Baldazzi L."xsd:string
http://purl.uniprot.org/citations/31344365http://purl.uniprot.org/core/author"Balsamo A."xsd:string
http://purl.uniprot.org/citations/31344365http://purl.uniprot.org/core/author"Greggio N.A."xsd:string
http://purl.uniprot.org/citations/31344365http://purl.uniprot.org/core/author"Menabo S."xsd:string
http://purl.uniprot.org/citations/31344365http://purl.uniprot.org/core/author"Karlsson L."xsd:string
http://purl.uniprot.org/citations/31344365http://purl.uniprot.org/core/author"Barbaro M."xsd:string
http://purl.uniprot.org/citations/31344365http://purl.uniprot.org/core/author"Guerra-Junior G."xsd:string
http://purl.uniprot.org/citations/31344365http://purl.uniprot.org/core/author"Lajic S."xsd:string
http://purl.uniprot.org/citations/31344365http://purl.uniprot.org/core/author"de Paula Michelatto D."xsd:string
http://purl.uniprot.org/citations/31344365http://purl.uniprot.org/core/author"Ostberg L.J."xsd:string
http://purl.uniprot.org/citations/31344365http://purl.uniprot.org/core/author"D'Almeida Mgnani Silva C."xsd:string
http://purl.uniprot.org/citations/31344365http://purl.uniprot.org/core/author"Lusa A.L.G."xsd:string
http://purl.uniprot.org/citations/31344365http://purl.uniprot.org/core/author"Palandi de Mello M."xsd:string
http://purl.uniprot.org/citations/31344365http://purl.uniprot.org/core/author"Valente de Lemos-Marini S.H."xsd:string
http://purl.uniprot.org/citations/31344365http://purl.uniprot.org/core/date"2019"xsd:gYear
http://purl.uniprot.org/citations/31344365http://purl.uniprot.org/core/name"Clin Biochem"xsd:string
http://purl.uniprot.org/citations/31344365http://purl.uniprot.org/core/pages"50-56"xsd:string
http://purl.uniprot.org/citations/31344365http://purl.uniprot.org/core/title"Novel non-classic CYP21A2 variants, including combined alleles, identified in patients with congenital adrenal hyperplasia."xsd:string
http://purl.uniprot.org/citations/31344365http://purl.uniprot.org/core/volume"73"xsd:string
http://purl.uniprot.org/citations/31344365http://www.w3.org/2004/02/skos/core#exactMatchhttp://purl.uniprot.org/pubmed/31344365
http://purl.uniprot.org/citations/31344365http://xmlns.com/foaf/0.1/primaryTopicOfhttps://pubmed.ncbi.nlm.nih.gov/31344365
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