p.H282N and p.Y191H: 2 novel CYP21A2 mutations in Italian congenital adrenal hyperplasia patients.
More than 90% of all cases of congenital adrenal hyperplasia (CAH) result from steroid 21-hydroxylase gene (CYP21A2) mutations. The CYP21A2 gene is located in the human leukocyte antigen (HLA) class III region on the short arm of chromosome 6p21.3, along with an inactive pseudogene, CYP21A1P, that is 98% homologous in its coding sequence with CYP21A2. Most CYP21A2 mutations result from intergenic recombinations between CYP21A2 and the closely linked CYP21A1P pseudogene. Rare mutations not generated by gene conversion account for only 5% to 10% of 21-hydroxylase deficiency alleles. However, detection of these rare and spontaneous mutations has continued to expand worldwide. We identified 2 novel CYP21A2 missense mutations (p.H282N and p.Y191H) in 2 Italian patients with simple-virilizing and nonclassic CAH forms. Functional analysis of these CYP21A2 mutations was performed. Functional in vitro assay for mutagenized CYP21A2 enzymes was performed in transiently transfected mammalian cells to test the residual enzyme activity and the apparent kinetic values. The residual activities obtained allowed us to classify the p.H282N and p.Y191H variants as simple-virilizing and nonclassic CAH associated mutations, respectively. These results correlate with the rate of severity of the patients' disease. This finding provides a further contribution for assisting in the diagnosis of CAH patients.
Laboratory of Molecular Biology, Institute of Biochemistry and Clinical Biochemistry, Catholic University, Largo A. Gemelli 8, 00168 Rome, Italy. paolaconcolino78@libero.it
Paola
P
Concolino
Enrica
E
Mello
Maria Cristina
MC
Patrosso
Silvana
S
Penco
Cecilia
C
Zuppi
Ettore
E
Capoluongo
D000312:Adrenal Hyperplasia, Congenital / Q000201:enzymology* / Q000235:genetics; D000328:Adult; D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D002522:Chlorocebus aethiops; D004247:DNA / Q000737:chemistry / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008297:Male; D016297:Mutagenesis, Site-Directed / Q000379:methods; D020125:Mutation, Missense; D013255:Steroid 21-Hydroxylase / Q000235:genetics*; D014162:Transfection
D004247:DNA; C531510:CYP21A2 protein, human; D013255:Steroid 21-Hydroxylase