Molecular basis of subtotal complement C6 deficiency. A carboxy-terminally truncated but functionally active C6.

Würzner, Reinhard; Hobart, M. J.; Fernie, B A; Mewar, Devesh; Potter, Paul; Orren, Ann; Lachmann, P. J.

doi:10.1172/jci117868

Cited by 52 publications

(34 citation statements)

References 35 publications

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“…In this report, we have also identified two patients and three healthy donors presenting combined C7SD(R499S)/C6SD alleles. A defect at the 5 0 splice donor site of intron 15 of the C6 gene explains the low molecular weight of the C6 protein and is responsible for its expression at low concentration [27]. In subjects homozygous for the C6SD mutation, the C6 level is about 1-5% of normal but retains hemolytic and bactericide properties [27,28].…”

Section: Discussionmentioning

confidence: 99%

“…A defect at the 5 0 splice donor site of intron 15 of the C6 gene explains the low molecular weight of the C6 protein and is responsible for its expression at low concentration [27]. In subjects homozygous for the C6SD mutation, the C6 level is about 1-5% of normal but retains hemolytic and bactericide properties [27,28]. The C7SD(R499S)/C6SD combined mutation characterizes a set of polymorphic DNA markers in the C6/C7 region, forming a distinct haplotype [29].…”

Section: Discussionmentioning

confidence: 99%

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Hereditary complement C7 deficiency in nine families: Subtotal C7 deficiency revisited

et al. 2007

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Deficiencies in terminal complement components, including the component C7, are uncommon and associated with an increased risk of recurrent systemic neisserial infection. A total of 22 molecular defects have been reported in the C7 gene with both complete (C7Q0) and subtotal (C7SD) C7 deficiencies. In this study we report the molecular basis of nine new cases of C7 deficiencies that were characterized by exonspecific sequence analysis. Seven different C7 gene mutations were identified corresponding to small deletions (n=2), splice site changes (n=1) and single base pair substitutions leading to nonsense (n=1) or missense (n=3) mutations. Altogether, three changes of the C7 gene (G357R, R499S and 5 0 splice donor site of intron 16) account for half of the molecular defects which emphasize that a restricted number of molecular abnormalities are involved in this deficiency. We identified two patients with combined C7Q0/C7SD(R499S) and established the C7SD(R499S) frequency at about 1% in normal Caucasian population. We demonstrated that C7(R499S) mutant protein is retained in the endoplasmic reticulum whereas the wild-type C7 is located in the Golgi apparatus. Our results provide evidence that R499S represents a loss-of-function polymorphism of C7 due to a defective folding of the protein.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Hereditary complement C7 deficiency in nine families: Subtotal C7 deficiency revisited

et al. 2007

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“…It has been hypothesized, but not proven, that the TSR modules in the complement proteins are involved in adhesion to each other and perhaps in the assembly of the MAC (34). Some support for this has been obtained from the inhibition of the assembly process by a monoclonal antibody specific for the third TSR module in C6 (35). Whether the (C 2 -Man-)Trp residues play a role in facilitating complex formation on the surface of the pathogen remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

The Four Terminal Components of the Complement System AreC-Mannosylated on Multiple Tryptophan Residues

Hofsteenge¹,

Blommers²,

Heß³

et al. 1999

Journal of Biological Chemistry

100

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C-Mannosylation is a unique form of protein glycosylation, involving the C-glycosidic attachment of a mannosyl residue to the indole moiety of Trp. In the two examples found so far, human RNase 2 and interleukin-12, only the first Trp in the recognition motif WXXW is specifically C-mannosylated. To establish the generality of protein C-mannosylation, and to learn more about its mechanism, the terminal components of the human complement system (C6, C7, C8,and C9), which contain multiple and complex recognition motifs, were examined. Together with C5b they form the cytolytic agent, the membrane attack complex. These are the first proteins that are C-mannosylated on more than one Trp residue as follows: six in C6, four in C7, C8␣, and C8␤, and two in C9. Thus, from the 113 Trp residues in the complete membrane attack complex, 50 were found to undergo C-mannosylation. The other important finding is that in C6, C7, C8, and C9 Trp residues without a second Trp (or another aromatic residue) at the ؉3 position can be C-mannosylated. This shows that they must contain an additional C-mannosylation signal. Whether this is encoded in the primary or tertiary structure is presently unknown. Finally, all modified Trp residues are part of the highly conserved core of the thrombospondin type 1 repeats present in these proteins. Since this module has been found in a large number of other proteins, the results suggest further candidates for C-mannosylation.

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“…Mutations of genes encoding the terminal components of complement (C5-C9) or its activating protein properdin (encoded by the X chromosome) were described between 1993 and 1998 (26)(27)(28)(29)(30)(31). A mutation in a gene encoding another activating protein, factor D, was first reported in 2001 (32).…”

Section: A Neglected Connection: Neisseria and Complementmentioning

confidence: 99%

Severe infectious diseases of childhood as monogenic inborn errors of immunity

Casanova

2015

Proc. Natl. Acad. Sci. U.S.A.

202

163

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This paper reviews the developments that have occurred in the field of human genetics of infectious diseases from the second half of the 20th century onward. In particular, it stresses and explains the importance of the recently described monogenic inborn errors of immunity underlying resistance or susceptibility to specific infections. The monogenic component of the genetic theory provides a plausible explanation for the occurrence of severe infectious diseases during primary infection. Over the last 20 y, increasing numbers of life-threatening infectious diseases striking otherwise healthy children, adolescents, and even young adults have been attributed to single-gene inborn errors of immunity. These studies were inspired by seminal but neglected findings in plant and animal infections. Infectious diseases typically manifest as sporadic traits because human genotypes often display incomplete penetrance (most genetically predisposed individuals remain healthy) and variable expressivity (different infections can be allelic at the same locus). Infectious diseases of childhood, once thought to be archetypal environmental diseases, actually may be among the most genetically determined conditions of mankind. This nascent and testable notion has interesting medical and biological implications.

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Molecular basis of subtotal complement C6 deficiency. A carboxy-terminally truncated but functionally active C6.

Cited by 52 publications

References 35 publications

Hereditary complement C7 deficiency in nine families: Subtotal C7 deficiency revisited

Hereditary complement C7 deficiency in nine families: Subtotal C7 deficiency revisited

The Four Terminal Components of the Complement System AreC-Mannosylated on Multiple Tryptophan Residues

Severe infectious diseases of childhood as monogenic inborn errors of immunity

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