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Novel deletion alleles carrying CYP21A1P/A2 chimeric genes in Brazilian patients with 21-hydroxylase deficiency.
BMC Med Genet. 2010 Jun 29; 11:104.BM

Abstract

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 ~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.

Authors+Show Affiliations

Laboratório de Genética Molecular Humana, Centro de Biologia Molecular e Engenharia Genética, Universidade Estadual de Campinas, Campinas, SP, Brasil.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20587039

Citation

Coeli, Fernanda B., et al. "Novel Deletion Alleles Carrying CYP21A1P/A2 Chimeric Genes in Brazilian Patients With 21-hydroxylase Deficiency." BMC Medical Genetics, vol. 11, 2010, p. 104.
Coeli FB, Soardi FC, Bernardi RD, et al. Novel deletion alleles carrying CYP21A1P/A2 chimeric genes in Brazilian patients with 21-hydroxylase deficiency. BMC Med Genet. 2010;11:104.
Coeli, F. B., Soardi, F. C., Bernardi, R. D., de Araújo, M., Paulino, L. C., Lau, I. F., Petroli, R. J., de Lemos-Marini, S. H., Baptista, M. T., Guerra-Júnior, G., & de-Mello, M. P. (2010). Novel deletion alleles carrying CYP21A1P/A2 chimeric genes in Brazilian patients with 21-hydroxylase deficiency. BMC Medical Genetics, 11, 104. https://doi.org/10.1186/1471-2350-11-104
Coeli FB, et al. Novel Deletion Alleles Carrying CYP21A1P/A2 Chimeric Genes in Brazilian Patients With 21-hydroxylase Deficiency. BMC Med Genet. 2010 Jun 29;11:104. PubMed PMID: 20587039.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Novel deletion alleles carrying CYP21A1P/A2 chimeric genes in Brazilian patients with 21-hydroxylase deficiency. AU - Coeli,Fernanda B, AU - Soardi,Fernanda C, AU - Bernardi,Renan D, AU - de Araújo,Marcela, AU - Paulino,Luciana C, AU - Lau,Ivy F, AU - Petroli,Reginaldo J, AU - de Lemos-Marini,Sofia H V, AU - Baptista,Maria T M, AU - Guerra-Júnior,Gil, AU - de-Mello,Maricilda P, Y1 - 2010/06/29/ PY - 2009/10/31/received PY - 2010/06/29/accepted PY - 2010/7/1/entrez PY - 2010/7/1/pubmed PY - 2010/9/17/medline SP - 104 EP - 104 JF - BMC medical genetics JO - BMC Med Genet VL - 11 N2 - 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 ~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. SN - 1471-2350 UR - https://www.unboundmedicine.com/medline/citation/20587039/Novel_deletion_alleles_carrying_CYP21A1P/A2_chimeric_genes_in_Brazilian_patients_with_21_hydroxylase_deficiency_ L2 - https://bmcmedgenet.biomedcentral.com/articles/10.1186/1471-2350-11-104 DB - PRIME DP - Unbound Medicine ER -