A novel missense mutation, GLY424SER, in Brazilian patients with 21-hydroxylase deficiency

A previous screening of 17 mutations in 130 Brazilian patients with congeni tal adrenal hyperplasia due to 21-hydroxylase deficiency did not identify m utations in 20% of the alleles. To diagnose these alleles we sequenced the entire CYP21 gene of one Mulatto patient with the simple virilizing form, w ho had only the R356W mutation in a heterozygous state. We identified a het erozygous G-->A transition in codon 424. This mutation leads to a substitut ion of glycine by serine in a conserved region where glycine is conserved i n at least 4 species. This novel mutation eliminates 1 of the restriction s ites of the BanI enzyme, which made its screening possible for the whole se ries. The G424S mutation was found in a compound heterozygous state in 5 fa milies; 4 presented the simple virilizing form, and 1 presented the nonclas sical form. Interestingly, 3 of 5 families have a Mulatto origin. This muta tion was not identified in 118 CYP21 alleles of normal individuals, ruling out the possibility of a polymorphism, or in 80 pseudogenes, indicating a c asual mutagenic event and not a micro-conversion event. All patients with t he G424S mutation presented CYP21P and C4A gene deletions and human leukocy te antigen DR17 on the same haplotype, suggesting a linkage disequilibrium and a probable founder effect. Search for the G424S mutation in other popul ations will reveal whether it is restricted to the Brazilian patients or if it has a wider ethnic distribution.