Reference Typing Report for Complement Components C6, C7 and C9 Including Mutations Leading to Deficiencies

Würzner, Reinhard; Witzel-Schlömp, Konstanze; Tokunaga, Katsushi; Fernie, B A; Hobart, M. J.; Orren, Ann

doi:10.1159/000019082

Cited by 27 publications

(33 citation statements)

References 47 publications

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“…Molecular characterization of 27 cases of total or subtotal C7 deficiencies have been previously reported and 22 different molecular defects in C7 gene are currently known [9][10][11][12][13]17]. Molecular mechanisms of nine new cases of C7 deficiency are reported in this study.…”

Section: Discussionmentioning

confidence: 78%

“…The protein has a normal molecular weight but exhibits an altered isoelectric point. Since C7SD was not found in the normal population by isoelectric focusing, it was considered as a mutation rather than a polymorphism in the C7 gene [9]. In this work we established for the first time a prevalence of the C7SD(R499S) variant in the healthy Caucasian population at approximately 1% by sequencing analysis.…”

Section: Discussionmentioning

confidence: 99%

“…To date, 22 molecular defects associated to complete (C7Q0) or subtotal (C7SD) C7 deficiencies have been reported. Five cases of C7SD resulting from R499S substitution and one case resulting from R198E, both defined by very low levels of C7, have been described [9][10][11][12][13]. The R499S mutation was reported alone or combined with a subtotal C6 deficiency (C6SD), a mutation located at the 5 0 splice donor site of intron 15 of the C6 gene, which also leads to very low levels of C6 [14].…”

Section: Introductionmentioning

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: 78%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2007

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“…Subtotal C6 deficiency in combination with subtotal C7 deficiency has been reported in two families (126). The C7 molecule in the patients with C6/C7 subtotal deficiency show an abnormal IEF pattern caused by an R499S mutation, and these patients have plasma C7 levels that are ϳ5% of normal (488,489). The same mutation was found in a Russian patient who had two episodes of meningococcal disease as a child.…”

Section: Inherited Deficiencies Of Complement Activationmentioning

confidence: 69%

“…This patient also had chronic otitis media that was only partially responsive to medical treatment; S. aureus and Bacteroides faecalis were cultured from middle ear pus (353). Complete deficiencies of C7 have been reported in several cases, and the molecular basis includes mutations at a 3Ј splice acceptor site in intron 1 (125), a mutation at a 5Ј splice donor site of intron 16, several point mutations (124,489), and deletion of part of the gene (326).…”

Section: Inherited Deficiencies Of Complement Activationmentioning

confidence: 99%

Infections of People with Complement Deficiencies and Patients Who Have Undergone Splenectomy

2010

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SUMMARY The complement system comprises several fluid-phase and membrane-associated proteins. Under physiological conditions, activation of the fluid-phase components of complement is maintained under tight control and complement activation occurs primarily on surfaces recognized as “nonself” in an attempt to minimize damage to bystander host cells. Membrane complement components act to limit complement activation on host cells or to facilitate uptake of antigens or microbes “tagged” with complement fragments. While this review focuses on the role of complement in infectious diseases, work over the past couple of decades has defined several important functions of complement distinct from that of combating infections. Activation of complement in the fluid phase can occur through the classical, lectin, or alternative pathway. Deficiencies of components of the classical pathway lead to the development of autoimmune disorders and predispose individuals to recurrent respiratory infections and infections caused by encapsulated organisms, including Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae. While no individual with complete mannan-binding lectin (MBL) deficiency has been identified, low MBL levels have been linked to predisposition to, or severity of, several diseases. It appears that MBL may play an important role in children, who have a relatively immature adaptive immune response. C3 is the point at which all complement pathways converge, and complete deficiency of C3 invariably leads to severe infections, including those caused by meningococci and pneumococci. Deficiencies of the alternative and terminal complement pathways result in an almost exclusive predisposition to invasive meningococcal disease. The spleen plays an important role in antigen processing and the production of antibodies. Splenic macrophages are critical in clearing opsonized encapsulated bacteria (such as pneumococci, meningococci, and Escherichia coli) and intraerythrocytic parasites such as those causing malaria and babesiosis, which explains the fulminant nature of these infections in persons with anatomic or functional asplenia. Paramount to the management of patients with complement deficiencies and asplenia is educating patients about their predisposition to infection and the importance of preventive immunizations and seeking prompt medical attention.

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C7 complement deficiency in an Israeli Arab village

et al. 2002

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Deficiencies of terminal complement components, particularly the latter ones, are often detected because of increased susceptibility to Neisserial infections. Herein we document the first report of C7 deficiency among a highly inbred Arab population living in the lower Galilee region of Israel. Both biochemical and molecular analysis were performed on samples from infected survivors and parents of children who succumbed to Neisserial infections in a 4-year period. Only the index case who suffered recurrent infections and a sibling who had not suffered an infection during the outbreak were found to be C7-deficient. The mutation was found to be the one previously described to be prevalent among Israeli Jews of Moroccan ancestry (mutation G1135C). The implications of this finding are discussed in the context of family pedigree, the protective effect of complement deficiency, and the clinical outcome.

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Reference Typing Report for Complement Components C6, C7 and C9 Including Mutations Leading to Deficiencies

Cited by 27 publications

References 47 publications

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

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

Infections of People with Complement Deficiencies and Patients Who Have Undergone Splenectomy

C7 complement deficiency in an Israeli Arab village

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