title: A novel missense mutation, GLY424SER, in Brazilian patients with 21-hydroxylase deficiency.
abstract: A previous screening of 17 mutations in 130 Brazilian patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency did not identify mutations in 20% of the alleles. To diagnose these alleles we sequenced the entire CYP21 gene of one Mulatto patient with the simple virilizing form, who had only the R356W mutation in a heterozygous state. We identified a heterozygous G-A transition in codon 424. This mutation leads to a substitution of glycine by serine in a conserved region where glycine is conserved in at least 4 species. This novel mutation eliminates 1 of the restriction sites of the BanI enzyme, which made its screening possible for the whole series. The G424S mutation was found in a compound heterozygous state in 5 families; 4 presented the simple virilizing form, and 1 presented the nonclassical form. Interestingly, 3 of 5 families have a Mulatto origin. This mutation was not identified in 118 CYP21 alleles of normal individuals, ruling out the possibility of a polymorphism, or in 80 pseudogenes, indicating a casual mutagenic event and not a microconversion event. All patients with the G424S mutation presented CYP21P and C4A gene deletions and human leukocyte antigen DR17 on the same haplotype, suggesting a linkage disequilibrium and a probable founder effect. Search for the G424S mutation in other populations will reveal whether it is restricted to the Brazilian patients or if it has a wider ethnic distribution.
authors.affiliation: Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo, Hospital das Clínicas, Brazil.
authors.forename: A E
authors.initials: AE
authors.lastname: Billerbeck
authors.forename: T A
authors.initials: TA
authors.lastname: Bachega
authors.forename: E T
authors.initials: ET
authors.lastname: Frazatto
authors.forename: M Y
authors.initials: MY
authors.lastname: Nishi
authors.forename: A C
authors.initials: AC
authors.lastname: Goldberg
authors.forename: M L
authors.initials: ML
authors.lastname: Marin
authors.forename: G
authors.initials: G
authors.lastname: Madureira
authors.forename: O
authors.initials: O
authors.lastname: Monte
authors.forename: I J
authors.initials: IJ
authors.lastname: Arnhold
authors.forename: B B
authors.initials: BB
authors.lastname: Mendonca
mesh_terms: D000312:Adrenal Hyperplasia, Congenital / Q000235:genetics*; D005260:Female; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D020125:Mutation, Missense; D016133:Polymerase Chain Reaction; D013255:Steroid 21-Hydroxylase / Q000235:genetics*
chemical_list: D013255:Steroid 21-Hydroxylase