A unique recombination event resulting in a C4A*Q0,C4B*Q0 double null haplotype.

Fasano, Mary Beth; Winkelstein, Jerry A.; LaRosa, Thomas; Bias, Wilma Β.; McLean, Robert H.

doi:10.1172/jci115978

Cited by 6 publications

(3 citation statements)

References 37 publications

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“…Polymorphisms in CYP21A1P pseudogene are known to be common [40], therefore those haplotypes could be originated from unequal crossovers involving bimodular alleles carrying different pseudogene variants. Recombination within 3'-end CYP21A2 seems to be frequent since it has been reported by different research groups [15,41] including as a de novo event in which deleted alleles were generated [48,49]. …”

Section: Discussionmentioning

confidence: 99%

Novel deletion alleles carrying CYP21A1P/A2chimeric genes in Brazilian patients with 21-hydroxylase deficiency

et al. 2010

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BackgroundCongenital 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.MethodsWe 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.ResultsAn 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.ConclusionsThis 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.

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Section: Discussionmentioning

confidence: 99%

Novel deletion alleles carrying CYP21A1P/A2chimeric genes in Brazilian patients with 21-hydroxylase deficiency

et al. 2010

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“…Among congenital adrenal hyperplasia patients, the reported frequency of de novo conversions is high in the intron 2 of the CYP21B gene (38). Also, a recombination event has been shown to produce a double null haplotype (C4AQ0,C4BQ0) leading to increased susceptibility to infections (39).…”

Section: Discussionmentioning

confidence: 99%

Characterization of a De Novo Conversion in Human Complement C4 Gene Producing a C4B5-Like Protein

Jaatinen

Eholuoto

Laitinen

et al. 2002

The Journal of Immunology

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Complement C4 is a highly polymorphic protein essential for the activation of the classical complement pathway. Most of the allelic variation of C4 resides in the C4d region. Four polymorphic amino acid residues specify the isotype and an additional four specify the Rodgers and Chido determinants of the protein. Rare C4 allotypes have been postulated to originate from recombination between highly homologous C4 genes through gene conversions. Here we describe the development of a de novo C4 hybrid protein with allotypic and antigenic diversity resulting from nonhomologous intra or interchromosomal recombination of the maternal chromosomes. A conversion was observed between maternal C4A3a and C4B1b genes producing a functional hybrid gene in one of the children. The codons determining the isotype, Asp1054, Leu1101, Ser1102, Ile1105 and His1106, were characteristic of C4B gene, whereas the polymorphic sites in exon and intron 28 were indicative of C4A3a sequence. The protein produced by this hybrid gene was electrophoretically similar to C4B5 allotype. It also possesses reversed antigenicity being Rodgers 1, 2, 3 and Chido-1, -2, -3, 4, -5, and -6. Our case describes the development of a rare bimodular C4B-C4B haplotype containing a functional de novo C4 hybrid gene arisen through gene conversion from C4A to C4B. Overall the data supports the hypothesis of gene conversions as an ongoing process increasing allelic diversity in the C4 locus.

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“…Prominently, it leads to the recombination between the CYP21A2 and the CYP21A1P to produce the CYP21A2 deficiency with congenital adrenal hyperplasia (Chu et al ., 1992) and the TNXA/TNXB genes with Ehlers–Danlos syndrome (Schalkwijk et al ., 2001). In addition, C4 gene recombination events have been shown to produce a double null haplotype (C4AQ0, C4BQ0), which increases susceptibility to infections (Fasano et al ., 1992) and a hybrid gene of the C4B5‐like protein (Jaatinen et al ., 2002).…”

Section: Introductionmentioning

confidence: 99%

An investigation of the C4 gene arrangement in ethnic Chinese (Taiwanese)

Tseng

Lee

2008

Int J Immunogenetics

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C4 complement components are encoded by two genes, C4A and C4B , located on chromosome 6p21.3 of the major histocompatibility complex class III region. The isotypic residues at position 1101-1106 of the C4A gene contain the Pro-Cys-Pro-Val-Leu-Asp sequence which has a higher affinity for binding amino group-containing antigens, while C4B contains the Leu-Ser-Pro-Val-Ileu-His sequence which has a higher affinity for hydroxyl group-containing antigens. These two genes show different reaction rates which infer solubilization of antibody-antigen aggregates and propagation of the activation pathway to form the membrane attack complex. Using a polymerase chain reaction-based amplification method to identify and differentiate the locations of the C4A and C4B genes adjacent to the respective CYP21A2P and CYP21A2 genes, the isotypic residues at position 1101-1106 for the C4 isotype were categorized into five haplotypes of C4 gene arrangements. Among them, we found that 65% of the gene proportions between C4A and C4B were balanced, while 35% of them were unbalanced in this ethnic Chinese (i.e. Taiwanese) cohort. We consider that the unbalanced arrangements of the C4 locus in the individuals might have influenced the clearance of apoptotic debris and immune complexes which may injure tissue by initiating autoimmune diseases and immunity responses associated with susceptibility to viral and bacterial infections.

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A unique recombination event resulting in a C4AQ0,C4BQ0 double null haplotype.

Cited by 6 publications

References 37 publications

Novel deletion alleles carrying CYP21A1P/A2chimeric genes in Brazilian patients with 21-hydroxylase deficiency

Novel deletion alleles carrying CYP21A1P/A2chimeric genes in Brazilian patients with 21-hydroxylase deficiency

Characterization of a De Novo Conversion in Human Complement C4 Gene Producing a C4B5-Like Protein

An investigation of the C4 gene arrangement in ethnic Chinese (Taiwanese)

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