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Report for Mutation D89E

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

There is one clinical trial.

Clinical Trials


1 Efferocytosis (Clearance of Apoptotic Cells by Phagocytosis) and Autoimmune Diseases in Human

Over the past few years, growing evidences revealed that clearance of apoptotic cells by phagocytosis can result in powerful anti-inflammatory and immunosuppressive effects. In vivo, apoptotic cells are cleared rapidly by neighboring cells, macrophages and related scavengers. Defective clearance of apoptotic cells has been linked closely to autoimmunity and persistent inflammatory disease. Several phagocytic receptors, bridging molecules produced by phagocytes and 'eat-me' signals on apoptotic cells are coordinately involved in mediating clearance of apoptotic cells. Complement receptors (CR3, CR4), collection, CD14, CD36 (Class B scavenger receptor), class A scavenger receptor, asialoprotein receptor, Mer receptor kinase were reported to recognize apoptotic cells. The best characterized system for clearance of apoptotic cells is the recognition of phosphatidylserine (PS) on apoptotic cells by phosphatidylserine receptor (PSR). Milk fat globule- epidermal growth factor 8 (MFG-E8) is an opsonin that bridges phagocytes (by interacting with α vβ3, αvβ5 integrins via RGD motif) and apoptotic cells (by binding PS through Factor V/VIII-C domain). Activated macrophages produce and secret MFG-E8. MFG-E8 is a critical component in PSR-mediated phagocytosis of apoptotic cells. The dominant negative mutant MFG-E8, D89E, that carried a mutated RGD motif inhibited phagocytosis of apoptotic cells in vitro. Injection of D89E into wild type mice induced autoantibodies and IgG deposition on glomeruli. Macrophages from MFG-E8 deficiency (MFG-E8-/-) mice were impaired in engulfment of apoptotic cells, which can be restored by adding recombinant MFG-E8. The female MFG-E8-/- mice spontaneously produced high titer of autoantibodies and developed lupus-like glomerulonephritis at the age of week 40. Defective clearance of apoptotic cells is closely related to development of autoimmunity. In the past 4 years, a growing number of molecules were recognized as receptors for the PS exposed on the apoptotic cells. These molecules were capable of mediating phagocytic clearance, rendering anti-inflammatory cytokines in the phagocytes, and modulating T cell responses. The specific aim of this proposal is to study genetic polymorphism in MFG-E8, PSR and other factors implicated in phagocytic clearance of apoptotic cells among Taiwanese. By comparing the polymorphism between patients with autoimmune disease (SLE or RA) and healthy control subjects, we will investigate if genetic variations among individuals of genes encoding proteins involved in clearance of apoptotic cells contribute to the pathogenesis of systemic autoimmune diseases SLE and RA.

NCT00364728 SLE Rheumatoid Arthritis Healthy Subjects
MeSH: Autoimmune Diseases
HPO: Autoimmunity

The dominant negative mutant MFG-E8, D89E, that carried a mutated RGD motif inhibited phagocytosis of apoptotic cells in vitro. --- D89E ---

Injection of D89E into wild type mice induced autoantibodies and IgG deposition on glomeruli. --- D89E ---

Kenichi et al. showed that masking phosphatidylserine by MFG-E8 mutant D89E, carrying a point mutation in RGD motif, inhibited not only the phagocytosis of apoptotic cells by macrophages of different origins but also the production of IL10 by thioglycollate-elicited peritoneal macrophages after phagocytosing apoptotic cells. --- D89E ---

When D89E MFG-E8 was injected into wild type mice intravenously, auto-antibodies were induced. --- D89E ---



HPO Nodes


Autoimmunity
Genes 223
DDX41 PTPN2 LACC1 MS4A1 FASLG LIG4 NFKB2 CASP10 STAT4 TCIRG1 POU2AF1 STOX1 TREX1 RFX5 WIPF1 RASGRP1 ITPR3 PRKCD C1GALT1C1 TNFRSF13B SERPING1 TBX1 PTPN22 STAT4 PEPD IL2RB POLG HLA-DRB1 GFI1 NBN ANKRD55 PTPN22 ANKRD55 TNFSF15 ICOS RFXANK TNFSF12 IFNGR1 C3 HLA-DQB1 FAS ITCH TNFAIP3 NRAS RFXAP TTC7A IL2RB IRF5 GPR35 SERPING1 STAT1 HLA-DPA1 CASP10 HLA-DRB1 SLC7A7 HIRA TNFRSF13B KDM6A SERPING1 CD3G DNASE1L3 ADA KMT2D SMPD1 CIITA HLA-DPB1 STAT4 LCK PRSS1 ICOS ITK IFIH1 CTLA4 PLCG2 HLA-DRB1 DNASE1 C1QC CSF2RA RAG1 CCR6 SPIB ARVCF RAG2 GALC TNFRSF13C ITCH DNASE1L3 MST1 SEC24C IL6 FCGR2A IL2RG PNP CR2 ADA JMJD1C MASP2 IL12RB1 IL2RB MMEL1 ZAP70 COMT UFD1 NBN STAT3 TNPO3 KRAS CD19 TREX1 TBX2 RAG1 AIRE HLA-DRB1 CORIN PTPN22 LMNB2 C1QB RAG1 TRAC SRP54 NHEJ1 FOXP3 TPP2 LRBA CCR6 HAVCR2 MMP2 FOXD3 CD247 TNFRSF13B MIF C1R GP1BB HNF1A DCLRE1C FAS ICOS CTLA4 CAV1 IL7R IRF5 CSF2RB TTC7A FCGR2B CAV1 SPP1 TNFRSF13C CTLA4 FADD CTLA4 IL7R C8A C1R ARHGEF1 RNASEH2B CD19 CR2 STAT1 FOXP3 CCN2 WAS IL2RA IL6 PTPN22 ADA2 PRKCD CCN2 ACP5 C2 SLC12A3 CFTR MTHFD1 C4A ADA2 PGM3 CHD7 KIAA0319L ADAR RREB1 RNASEH2C PTPN22 C1QA TCF4 IL12A RNASEH2A CD247 BTK FCGR2C ADA2 FAS C1QA CD81 PAX4 RAG2 C1S IRAK1 PRKCD ELANE TREX1 NFKB1 ZAP70 SEC23B NLRP1 PTEN TNFSF12 FLT1 ADA FASLG PIK3R1 STIM1 IRF5 CLCNKB IL2RA CTRC PRTN3 IL2RA TBX1 RMRP SPINK1 SAMHD1 PTPN2 NFKB2 DCLRE1C