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H28+C Insertion in the CYP21 Gene: A Novel Frameshift Mutation in a Brazilian Patient with the Classical Form of 21-Hydroxylase Deficiency

Centro de Biologia Molecular e Engenharia Genética (I.F.L., F.C.S., M.P.D.M.); Departamento de Pediatria/Centro de Investigação em Pediatria (S.H.V.L.-M., G.G.); and Disciplina de Endocrinologia-Faculdade de Ciências Médicas (M.T.M.B.), Universidade Estadual de Campinas, 13083-970 Campinas, São Paulo, Brasil

Address all correspondence and requests for reprints to: Maricilda Palandi de Mello, Ph.D., Centro de Biologia Molecular e Engenharia Genética, Universidade Estadual de Campinas, Caixa Postal 6010, CEP 13083-970, Campinas, SP Brasil. E-mail: mmello{at}obelix.unicamp.br

Abstract

In the classical form of 21-hydroxylase deficiency, CYP21- affected genes either carry mutations present in the CYP21P pseudogene (microconversions) or bear a chimeric gene that replaces the active gene as a result of large conversion or deletion mutational events. Previous genotyping of 41 Brazilian patients revealed 64% microconversion, whereas deletions and large gene conversions accounted for up to 21% of the molecular defect. The present paper describes a new mutation disclosed by sequencing an entire gene in which no pseudogene-originated mutation had been found. The patient with the classical form of 21-hydroxylase deficiency is the daughter of a consanguineous marriage, and she is homozygous for a novel frameshift H28+C within exon 1. The mutation causes a stop codon at amino acid 78. Both parents are heterozygous for the mutation as confirmed by allele-specific oligonucleotide PCR. The H28+C is not present in the published CYP21P sequences and is likely to result in an enzyme with no activity.

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