Genetic basis of human complement C4A deficiency. Detection of a point mutation leading to nonexpression.

Barba, Giovanna; Rittner, Christian; Schneider, P. M.

doi:10.1172/jci116377

Cited by 75 publications

(48 citation statements)

References 31 publications

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“…Pelo menos 40 alelos para cada gene já foram relatados, incluindo os alelos nulos, C4A*Q0 e C4B*Q0, responsáveis pela ausência da proteína C4A e C4B no soro (Q = quantidade zero) (26) . Apesar da maior parte dos casos de alelos nulos ser devida à deleção do gene, aproximadamente 40% deles decorre da não-expressão de genes não alterados (28) . Alelos nulos de C4A ou C4B ocorrem com uma freqüência de 10% a 20% em diferentes populações (20) .…”

Section: O Complemento Na Patogenia Das Doençasunclassified

O sistema complemento nas doenças: genética e patogenia

Utiyama¹,

Reason²,

Kotze³

2004

Rev. Bras. Reumatol.

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O Sistema Complemento nas Doenças: Genética e Patogenia 277ARTIGO DE REVISÃO REVIEW ARTICLE RESUMOO sistema complemento é parte fundamental da imunidade inata e contribui na remoção de complexos imunes e na ativação de processos inflamatórios. Essas proteínas representam um meio rápido e eficiente de proteção do hospedeiro contra microorganismos invasores. Associações entre complemento e doenças são observadas em situações de deficiência do complemento, anormalidades na regulação do complemento e nas inflamações. Ativação imprópria ou excessiva do complemento pode levar a conseqüências lesivas em virtude da grave destruição tecidual inflamatória. Evidências clínicas e experimentais ressaltam o papel do complemento na patogênese de inúmeras doenças inflamatórias, que incluem não apenas doenças por imune-complexos e auto-imunes, como também falência de órgãos subseqüentes a sepse, traumas múltiplos e queimaduras. O polimorfismo genético tem sido descrito para diversos componentes de membrana, proteínas solúveis de controle e receptores do sistema complemento. Atualmente, o polimorfismo dos componentes do complemento pode ser estudado usualmente, tanto pela pesquisa fenotípica das variantes protéicas (fenotipagem) como pela caracterização genômica do DNA (genotipagem), e tem contribuído para o entendimento da patogênese de diferentes enfermidades. Doenças imunologicamente mediadas estão associadas às variantes alotípicas do complemento, em particular lúpus eritematoso sistêmico, artrite reumatóide, esclerose múltipla, doença celíaca, deficiência de IgA e IgG4, entre outras. A presente revisão tem por objetivo dar uma visão dos conhecimentos atuais na área da genética do complemento, bem como da participação desse sistema na patogenia de diferentes doenças.

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Section: O Complemento Na Patogenia Das Doençasunclassified

O sistema complemento nas doenças: genética e patogenia

Utiyama¹,

Reason²,

Kotze³

2004

Rev. Bras. Reumatol.

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“…Oligonucleotides of human C4 and RCCX constituents were designed based on published DNA sequences (51)(52)(53) 1,3,4,5,6,8,9,10,11,12,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,31,32,33,34,35,37,38,39,40, and 41. The primers were designed based on the genomic DNA sequence of C4A3a (51).…”

Section: Synthetic Dna Primersmentioning

confidence: 99%

“…The presence of a 2-bp insertion in C4A exon 29 (21) or C4B exon 29 (24) was detected via PCR using synthetic PCR primer pairs A-down and C4INS, and B-down and C4INS, respectively. PCR was performed with Taq DNA polymerase (Life Technologies).…”

Section: Sequence-specific Pcr To Detect C4 Mutationsmentioning

confidence: 99%

“…Close to 30% of the normal population have relatively lower levels of either C4A or C4B proteins caused by the presence of only one C4A gene or only one C4B gene in a diploid genome (5,19,20). Also, in HLA A2 Cw3 B60 DR6 haplotypes with bimodular LS structures for RCCX, the long C4A gene does not code for a protein product whereas the short C4B gene codes for C4B1 or C4B2 protein (21). The mutant C4A gene, C4AQ0, is caused by frame-shift mutations due to a dinucleotide insertion in exon 29 at the sequence for codon 1213.…”

mentioning

confidence: 99%

“…The mutant C4A gene, C4AQ0, is caused by frame-shift mutations due to a dinucleotide insertion in exon 29 at the sequence for codon 1213. This specific mutation has been detected in both healthy Caucasians and those with autoimmune disease (5,(21)(22)(23)(24).…”

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confidence: 99%

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The Molecular Basis of Complete Complement C4A and C4B Deficiencies in a Systemic Lupus Erythematosus Patient with HomozygousC4AandC4BMutant Genes

Rupert

Moulds

Yang

et al. 2002

The Journal of Immunology

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The disease course of a complete C4-deficient patient in the U.S. was followed for 18 years. The patient experienced multiple episodes of infection, and he was diagnosed with systemic lupus erythematosus at age 9 years. The disease progressed to WHO class III mild lupus nephritis and to fatal CNS vasculitis at age 23 years. Immunochemical experiments showed that the patient and his sibling had complete absence of C4A and C4B proteins and were negative for the Rodgers and Chido blood group Ags. Segregation and definitive RFLP analyses demonstrated that the patient and his sibling inherited two identical haplotypes, HLA A2 B12 DR6, each of which carries a defective long C4A gene and a defective short C4B gene. PCR and DNA sequencing revealed that the mutant C4A contained a 2-bp insertion in exon 29 at the sequence for codon 1213. The identical mutation was absent in the mutant C4B. The C4B mutant gene was selectively amplified by long range PCR, and its 41 exons were completely sequenced. The C4B mutant had a novel single C nucleotide deletion at the sequence for codon 522 in exon 13, leading to frame-shift mutation and premature termination. Thus, a multiplex PCR is designed by which known mutations in C4A and C4B can be elucidated conveniently. Among the 28 individuals reported with complete C4 deficiency, 75–96% of the subjects (dependent on the inclusion criteria) were afflicted with autoimmune or immune complex disorders. Hence, complete C4 deficiency is one of the most penetrant genetic risk factors for human systemic lupus erythematosus.

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Human Complement Components C4A and C4B Genetic Diversities: Complex Genotypes and Phenotypes

Chung

Yang

et al. 2005

CP in Immunology

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This unit describes methods that can accurately determine the genotypes and phenotypes of human complement components C4A and C4B. Specifically, they allow investigators to determine how many C4 genes are present in a diploid genome of a human subject and to quantify how many of them encode C4A proteins and how many of them encode C4B proteins. In addition, methods to determine how many long and short C4 genes are present in a diploid genome of a subject are described together with experimental strategies to determine haplotypes and order or configuration of these genes in the MHC. Finally, methods to assess the degree of polymorphism in C4A and C4B proteins and whether low protein levels of plasma C4 may be caused by low C4 gene dosages and/or by mutant C4 genes.

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Genetic basis of human complement C4A deficiency. Detection of a point mutation leading to nonexpression.

Cited by 75 publications

References 31 publications

O sistema complemento nas doenças: genética e patogenia

O sistema complemento nas doenças: genética e patogenia

The Molecular Basis of Complete Complement C4A and C4B Deficiencies in a Systemic Lupus Erythematosus Patient with HomozygousC4AandC4BMutant Genes

Human Complement Components C4A and C4B Genetic Diversities: Complex Genotypes and Phenotypes

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