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A Novel Missense Mutation, GLY424SER, in Brazilian Patients with 21-Hydroxylase Deficiency¹

Unidade de Endocrinologia do Desenvolvimento e Laboratório de Hormônios e Genética Molecular da Disciplina de Endocrinologia-LIM/42, Faculdade de Medicina da Universidade de São Paulo, Hospital das Clínicas, Sao Paulo, Brazil

Address all correspondence and requests for reprints to: Berenice B. Mendonca, M.D., Faculdade de Medicina da Universidade de São Paulo, Divisão de Endocrinologia, Hospital das Clínicas, Caixa Postal 3671, Sao Paulo CEP 01060–970, Brazil. E-mail: beremen{at}usp.br

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 GA 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.

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