Chromosomal assignment of genes encoding the α, β, and γ subunits of human complement protein C8: Identification of a close physical linkage between the α and the β loci

Kaufman, Kenneth M.; Snider, James V.; Spurr, Nigel K.; Schwartz, Charles E.; Sodetz, James M.

doi:10.1016/0888-7543(89)90012-8

Cited by 44 publications

(18 citation statements)

References 25 publications

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“…Deficiency of C8a--y is associated with less C8,B in serum than occurs in normal individuals (356). At present, it is unclear whether the reduction in C8 reflects the tight 5'-3' linkage between the C8a and C8,B loci (190) or stems from a posttranslational requirement of C8a--y for either C8,B secretion or protection from intracellular proteolysis.…”

Section: Microbial Interactions With Complementmentioning

confidence: 92%

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Infectious diseases associated with complement deficiencies

1991

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The complement system consists of both plasma and membrane proteins. The former influence the inflammatory response, immune modulation, and host defense. The latter are complement receptors, which mediate the cellular effects of complement activation, and regulatory proteins, which protect host cells from complement-mediated injury. Complement activation occurs via either the classical or the alternative pathway, which converge at the level of C3 and share a sequence of terminal components. Four aspects of the complement cascade are critical to its function and regulation: (i) activation of the classical pathway, (ii) activation of the alternative pathway, (iii) C3 convertase formation and C3 deposition, and (iv) membrane attack complex assembly and insertion. In general, mechanisms evolved by pathogenic microbes to resist the effects of complement are targeted to these four steps. Because individual complement proteins subserve unique functional activities and are activated in a sequential manner, complement deficiency states are associated with predictable defects in complement-dependent functions. These deficiency states can be grouped by which of the above four mechanisms they disrupt. They are distinguished by unique epidemiologic, clinical, and microbiologic features and are most prevalent in patients with certain rheumatologic and infectious diseases. Ethnic background and the incidence of infection are important cofactors determining this prevalence. Although complement undoubtedly plays a role in host defense against many microbial pathogens, it appears most important in protection against encapsulated bacteria, especially Neisseria meningitidis but also Streptococcus pneumoniae, Haemophilus influenzae, and, to a lesser extent, Neisseria gonorrhoeae. The availability of effective polysaccharide vaccines and antibiotics provides an immunologic and chemotherapeutic rationale for preventing and treating infection in patients with these deficiencies.

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Section: Microbial Interactions With Complementmentioning

confidence: 92%

“…Similarly, C8, and C8ot are tightly linked on the short arm of chromosome 1 (190). Whereas individuals with reported C8 deficiency have been predominantly Caucasian, persons with C8ot--y deficiency are predominantly black or Hispanic (Table 3 (254).…”

Section: Microbial Interactions With Complementmentioning

confidence: 99%

Infectious diseases associated with complement deficiencies

1991

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“…1-lp36.3 (Sellar & Reid, 1989), but the direction of transcription and order of the genes with respect to the centromere is as yet unknown. Two other clusters of genes for proteins associated with the complement system are known to lie on chromosome 1: (i) the genes of the regulators of complement activation (RCA) locus at 1q32, which includes the a-and f-chains of C4-binding protein, complement receptor 1, complement receptor 2, decay acceleration factor, membrane cofactor protein and Factor H (Rey-Campos et al, 1988;PardoManuel et al, 1990); (ii) the a-and f-chains of the terminal attack component C8, within 2.5 kb of each other, in the lp region (Kaufman et al, 1989). However, the RCA locus is clearly quite distant from the genes encoding the chains of Clq, and further mapping studies are required to determine whether the C8 a-chain and ,-chain genes are relatively close to the Clq genes, although lack of similarity in amino acid sequence between the chains of C8 and the chains of Clq indicates the proteins are not related.…”

Section: Discussionmentioning

confidence: 99%

Characterization and organization of the genes encoding the A-, B- and C-chains of human complement subcomponent C1q. The complete derived amino acid sequence of human C1q

Sellar

Blake

1991

Biochemical Journal

204

120

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A partial cDNA clone for the A-chain of human complement subcomponent Clq was isolated from a monocyte library. Use of the A-chain cDNA clone, and a previously characterized B-chain cDNA clone [Reid (1985) Biochem. J. 231, 729-735] allowed the isolation of overlapping cosmid clones that were shown to contain the genes encoding the A-, Band C-chains of human Clq. The three genes were found to be aligned, 5'-.3', in the same orientation, in the order A-C-B on a 24 kb stretch of DNA on chromosome lp. The A-, B-and C-chain genes are approx. 2.5, 2.6 and 3.2 kb long respectively, and each contains one intron, located within a codon for a glycine residue found half-way along the collagenlike region present in each chain. These glycine residues are located just before the point where the triple-helical portions of the Clq molecule appear to bend when viewed in the electron microscope. Southern-blot analyses indicated that there is only one gene per chain, and preliminary examination of genomic DNA from several Cl q-deficient patients showed no evidence for major deletions or insertions within the A-, B-or C-chain genes. The DNA sequence of the coding region of the C-chain gene allows the completion of the entire derived amino acid sequence for the human Clq molecule. The globular, C-terminal, regions of the chains of Clq show a strong similarity in amino acid sequence to the non-collagenlike, C-terminal, regions of the type VIII and type X collagens, indicating structural and evolutionary relationships between these three molecules.

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“…A major deletion of the # gene has been excluded based on studies of genomic DNA from patients with C8(3 deficiency (21), while for the combined deficiency the defect may be in a or y. A major gene deletion in a seems unlikely in view of the close physical linkage between a and (3 on chromosome 1 and the expression of functional (3 in the C8a-yD (22). The exact nature of the a-'y defect must await further characterization of a and y genomic structures.…”

Section: Discussionmentioning

confidence: 99%

Two distinct abnormalities in patients with C8 alpha-gamma deficiency. Low level of C8 beta chain and presence of dysfunctional C8 alpha-gamma subunit.

et al. 1990

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The sera from three C8a-"y deficient patients previously reported to have a selective C8a--y defect were analyzed by SDS-PAGE and Western blot using two polyclonal antisera to C8a-y and a monoclonal antibody to C8a. All three sera exhibited C8a-'y bands that dissociated into a and y chains under reducing conditions. Quantitation of the a-'y subunit in these sera by a sensitive ELISA revealed an amount -1% of that found in normal human serum. A similar assay performed with a specific antiserum to C8,0 showed unexpectedly low levels of C8,B in these sera, which were confirmed by hemolytic titration of C8ft. The remarkable differences between C8a-'y and C8# in

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Chromosomal assignment of genes encoding the α, β, and γ subunits of human complement protein C8: Identification of a close physical linkage between the α and the β loci

Cited by 44 publications

References 25 publications

Infectious diseases associated with complement deficiencies

Infectious diseases associated with complement deficiencies

Characterization and organization of the genes encoding the A-, B- and C-chains of human complement subcomponent C1q. The complete derived amino acid sequence of human C1q

Two distinct abnormalities in patients with C8 alpha-gamma deficiency. Low level of C8 beta chain and presence of dysfunctional C8 alpha-gamma subunit.

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