Complement regulator CD46: genetic variants and disease associations

Liszewski, M. Kathryn; Atkinson, John P.

doi:10.1186/s40246-015-0029-z

Cited by 88 publications

(101 citation statements)

References 86 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This family along with two others carrying MCP variants were reported in 2003 (20). There have now been several hundred variants identified in the CFH gene and over 60 in MCP (15, 22, 23). Many loss-of-function variants in FI and a few gain-of-function variants in C3 and FB have also been described (reviewed in 15, 22, 24).…”

Section: Complement System Dysregulation and Diseasementioning

confidence: 99%

“…Furthermore, it does not bind C3b or C3b-bearing complexes found in the fluid phase (plasma). More than 60 disease-associated CD46 mutations have been identified; most all of these are rare and deleterious, and associated with the development of aHUS (22) ( Figure 5 ).…”

Section: Membrane Cofactor Protein Mutationsmentioning

confidence: 99%

“…In addition, variants of MCP have been increasingly associated with inflammatory disorders, especially those characterized by development of thrombi in small blood vessels, particularly aHUS (22, 23, 80–83). The majority of aHUS disease-associated mutations occur in the four CCPs.…”

Section: Membrane Cofactor Protein Mutationsmentioning

confidence: 99%

See 2 more Smart Citations

Complement Dysregulation and Disease: Insights from Contemporary Genetics

Liszewski

Java

Schramm³

et al. 2017

Annu. Rev. Pathol. Mech. Dis.

Self Cite

View full text Add to dashboard Cite

The vertebrate complement system consists of sequentially interacting proteins that provide for a rapid and powerful host defense. Nearly 60 proteins comprise three activation pathways (classical, alternative, and lectin) and a terminal cytolytic pathway common to all. Attesting to its potency, nearly half of the system’s components are engaged in its regulation. An emerging theme over the past decade is that variations in these inhibitors predispose to two scourges of modern humans. One, occurring most often in childhood, is a rare but deadly thrombomicroangiopathy called atypical hemolytic uremic syndrome. The other, age-related macular degeneration, is the most common form of blindness in the elderly. Their seemingly unrelated clinical presentations and pathologies share the common theme of overactivity of the complement system’s alternative pathway. This review summarizes insights gained from contemporary genetics for understanding how dysregulation of this powerful innate immune system leads to these human diseases.

show abstract

Section: Complement System Dysregulation and Diseasementioning

confidence: 99%

Section: Membrane Cofactor Protein Mutationsmentioning

confidence: 99%

See 1 more Smart Citation

Complement Dysregulation and Disease: Insights from Contemporary Genetics

Liszewski

Java

Schramm³

et al. 2017

Annu. Rev. Pathol. Mech. Dis.

Self Cite

View full text Add to dashboard Cite

show abstract

“…CD46, the membrane cofactor protein, and CD55, the decay-accelerating factor, target C3b and the C3/C5 convertases (9,10). CD59 prevents MAC formation by binding to C8 and C9 during MAC assembly (11).…”

mentioning

confidence: 99%

Regulation of Complement-Dependent Cytotoxicity by MicroRNAs miR-200b, miR-200c, and miR-217

Hillman

Mazkereth

Farberov

et al. 2016

The Journal of Immunology

View full text Add to dashboard Cite

The impact of microRNAs (miRNAs) known to regulate numerous biologic processes on complement-dependent cytotoxicity (CDC) was investigated in K562 cells. The C5b-9 complex is the executioner of CDC. Cells protect themselves from CDC by C5b-9 elimination, a process involving the mitochondrial chaperone mortalin/GRP75. Potential miR-200 (b and c) and miR-217 regulatory sites were identified in mortalin mRNA. Overexpression of miR-200b/c or miR-217 lowered the expression of mortalin mRNA. miRNA inhibitors for miR-200b, miR-200c, or miR-217 enhanced mortalin mRNA level. Unexpectedly, these miRNA modulators had no significant effect on mortalin protein level. Metabolic labeling analysis demonstrated that, to compensate for reduction in mortalin mRNA level, the cells increased the rate of synthesis of mortalin protein. Cells overexpressing miR-200b/c or miR-217 showed reduced sensitivity to CDC, whereas inhibition of miR-200c and miR-217 enhanced cell death. miR-200b/c overexpression reduced C5b-9 binding and enhanced its release from the cells and promoted mortalin relocation to the plasma membrane. Inhibition of miR-200 (b and c) and miR-217 had no effect on the expression level of the membrane complement-regulatory proteins CD46, CD55, and CD59. However, overexpression of miR-200b/c or miR-217 enhanced expression of CD46 and CD55 (not of CD59). Overall, the data demonstrate miRNA regulation of cell sensitivity to CDC. We identified miR-200b, miR-200c, and miR-217 as regulators of mortalin and, perhaps indirectly, of CD46 and CD55. Cell exposure to a sublytic dose of complement was shown to increase expression of miR-200 (b and c), suggesting that complement C5b-9 exerts a feedback-regulatory effect on these miRNAs.

show abstract

“…Along with hemostatic parameters they found a reduction in HLA-DR expression in PVT-groups and increased levels of monocyte co-stimulatory molecule CD46 independently by the presence of cirrhosis. These indexes of profound immunological disturbance (15,16) are coherent, although not specific, with the link between immune-system and hemostasis and warrant further investigations. The absence of differences between cirrhotic and non-cirrhotic PVT suggests the determinant role of immune system in the susceptibility to PVT whatever the degree of liver damage.…”

mentioning

confidence: 96%