Nobel deletion alleles carrying CYP21A1P/A2 chimeric genes in Brazilian patients with 21-hydroxylase deficiency

Autor(es):Mostrar menos -

Coeli, Fernanda B. ^[1] ; Soardi, Fernanda C. ^[1] ; Bernardi, Renan D. ^[1] ; de Araujo, Marcela ^[1] ; Paulino, Luciana C. ^[1] ; Lau, Ivy F. ^[1] ; Petroli, Reginaldo J. ^[1] ; de Lemos-Marini, Sofia H. V. ^[2] ; Baptista, Maria T. M. ^[3] ; Guerra-Junior, Gil ^[2] ; de-Mello, Maricilda P. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Estadual Campinas, Lab Genet Mol Humana, Ctr Biol Mol & Engn Genet, Campinas, SP - Brazil

^[2] Univ Estadual Campinas, Fac Ciencias Med, Dept Pediat, Ctr Invest Pediat, Campinas, SP - Brazil

^[3] Univ Estadual Campinas, Fac Ciencias Med, Dept Clin Med, Disciplina Endocrinol, Campinas, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: BMC MEDICAL GENETICS; v. 11, JUN 29 2010.
• Citações Web of Science: 8

Resumo

Background: Congenital adrenal hyperplasia due to 21-hydroxylase deficiency is caused by deletions, large gene conversions or mutations in CYP21A2 gene. The human gene is located at 6p21.3 within a locus containing the genes for putative serine/threonine Kinase RP, complement C4, steroid 21-hydroxylase CYP21 tenascin TNX, normally, in a duplicated cluster known as RCCX module. The CYP21 extra copy is a pseudogene (CYP21A1P). In Brazil, 30-kb deletion forming monomodular alleles that carry chimeric CYP21A1P/A2 genes corresponds to similar to 9% of disease-causing alleles. Such alleles are considered to result from unequal crossovers within the bimodular C4/CYP21 locus. Depending on the localization of recombination breakpoint, different alleles can be generated conferring the locus high degree of allelic variability. The purpose of the study was to investigate the variability of deleted alleles in patients with 21-hydroxylase deficiency. Methods: We used different techniques to investigate the variability of 30-kb deletion alleles in patients with 21-hydroxylase deficiency. Alleles were first selected after Southern blotting. The composition of CYP21A1P/A2 chimeric genes was investigated by ASO-PCR and MLPA analyses followed by sequencing to refine the location of recombination breakpoints. Twenty patients carrying at least one allele with C4/CYP21 30-kb deletion were included in the study. Results: An allele carrying a CYP21A1P/A2 chimeric gene was found unusually associated to a C4B/C4A Taq I 6.4-kb fragment, generally associated to C4B and CYP21A1P deletions. A novel haplotype bearing both p.P34L and p.H62L, novel and rare mutations, respectively, was identified in exon 1, however p.P30L, the most frequent pseudogene-derived mutation in this exon, was absent. Four unrelated patients showed this haplotype. Absence of p.P34L in CYP21A1P of normal controls indicated that it is not derived from pseudogene. In addition, the combination of different approaches revealed nine haplotypes for deleted 21-hydroxylase deficiency alleles. Conclusions: This study demonstrated high allelic variability for 30-kb deletion in patients with 21-hydroxylase deficiency indicating that a founder effect might be improbable for most monomodular alleles carrying CYP21A1P/A2 chimeric genes in Brazil. (AU)

• Processo FAPESP: 97/07622-2 - Caracterização molecular de alelos raros relacionados com a deficiência da 21-hidroxilase
• Beneficiário: Maricilda Palandi de Mello
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 05/00981-5 - Hiperplasia congênita da adrenal: mutações novas e suas alterações na atividade enzimática
• Beneficiário: Maricilda Palandi de Mello
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 01/08150-4 - Deficiencia de 21-hidroxilase: mutacoes recorrentes - mesmos alelos.
• Beneficiário: Maricilda Palandi de Mello
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 92/03332-6 - Identificação e caracterização de mutações relativas à deficiência da 21-hidroxilase em 21 famílias
• Beneficiário: Maricilda Palandi de Mello
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 03/01785-0 - Mutações novas em genes esteroidogênicos e suas alterações na atividade enzimática
• Beneficiário: Fernanda Caroline Soardi
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto