ANALYSIS OF STEROID 21-HYDROXYLASE GENE-MUTATIONS IN THE SPANISH POPULATION

Steroid 21-hydroxylase deficiency is the major cause of congenital adr enal hyperplasia. Genotyping for deletions and nine point mutations in the CYP21 gene has been performed in 38 Spanish patients and their re latives by Southern blot analysis and allele-specific oligonucleotide hybridization. Three clinical variants were included in this study, vi z., salt-wasting (SW, 21 patients), simple virilizer (SV, two patients ), and late-onset (LO, 15 patients) forms. Twenty-three patient genoty pes (16 SW, two SV, and five LO) were fully characterized. In both all eles, all but one of these severe forms (SW and SV) presented mutation s that abolished or severely affected enzymatic activity. Patients wit h LO forms showed mutations that moderately impaired enzymatic activit y in both alleles, or severe mutations in only one chromosome. Of 46 c hromosomes from severe forms, 41 were characterized in this study (89% ). The most frequent mutation was an aberrant splicing site (655 A or C to G) in intron 2, in 30% of these chromosomes. Deletions were found in 20%, and large gene conversions in 13% of these alleles. This scre ening allowed the characterization of 18 out of 30 LO chromosomes, the most frequent mutation being Val281Leu (37%). Severe mutations were f ound, in heterozygosis, in one third of LO patients.