Structure-based analysis of five novel disease-causing mutations in 21-hydroxylase-deficient patients.
Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is the most frequent inborn error of metabolism, and accounts for 90-95% of CAH cases. The affected enzyme, P450C21, is encoded by the CYP21A2 gene, located together with a 98% nucleotide sequence identity CYP21A1P pseudogene, on chromosome 6p21.3. Even though most patients carry CYP21A1P-derived mutations, an increasing number of novel and rare mutations in disease causing alleles were found in the last years. In the present work, we describe five CYP21A2 novel mutations, p.R132C, p.149C, p.M283V, p.E431K and a frameshift g.2511_2512delGG, in four non-classical and one salt wasting patients from Argentina. All novel point mutations are located in CYP21 protein residues that are conserved throughout mammalian species, and none of them were found in control individuals. The putative pathogenic mechanisms of the novel variants were analyzed in silico. A three-dimensional CYP21 structure was generated by homology modeling and the protein design algorithm FoldX was used to calculate changes in stability of CYP21A2 protein. Our analysis revealed changes in protein stability or in the surface charge of the mutant enzymes, which could be related to the clinical manifestation found in patients.
Centro Nacional de Genética Médica, ANLIS, Buenos Aires, Argentina.
Carolina
C
Minutolo
Alejandro D
AD
Nadra
Cecilia
C
Fernández
Melisa
M
Taboas
Noemí
N
Buzzalino
Bárbara
B
Casali
Susana
S
Belli
Eduardo H
EH
Charreau
Liliana
L
Alba
Liliana
L
Dain
D000312:Adrenal Hyperplasia, Congenital / Q000235:genetics*; D000465:Algorithms; D001118:Argentina; D016022:Case-Control Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D055550:Protein Stability; D013255:Steroid 21-Hydroxylase / Q000737:chemistry* / Q000235:genetics*
C531510:CYP21A2 protein, human; D013255:Steroid 21-Hydroxylase
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