β6 integrinosis: a new lethal autosomal recessive ITGB6 disorder leading to impaired conformational transitions of the α_Vβ6 integrin receptor

Abstract

Figure 1 (A) Pedigree tree: patient (arrow) and known relatives. Red: verified ITGB6G1312A|rs61737764. (B) Immunohistochemistry/H&E stain on parallel target/control tissue sections using anti-human α V β6 (6.2A1) or anti-human LTBP1 (Antibodies Online/ABIN1807165).

Reply

“…5 In addition, patients with autosomal recessive integrin b6 mutation disorder have infantile intractable diarrhea. 6 Taken together, these findings suggest that anti-integrin aVb6 autoantibodies may have a pathogenic role in UC, by either directly blocking the functions of integrin aVb6 or eliciting complement-mediated epithelial cell injury. As for anti-EPCR autoantibodies, Mutoh et al 2 showed that anti-EPCR Q7 antibodies enhanced human endothelial activation and promoted Th17 differentiation of CD4 T cells, suggesting a pathogenic role of anti-EPCR antibodies in vascular inflammation.…”

Insights into Protein–Ligand Interactions in Integrin Complexes: Advances in Structure Determinations

“…Recently, αvβ6 has been intensively investigated for cancer therapy/cancer imaging and treatment of IPF . A V438M mutation in ITGB6 has been attributed as the cause for β6 integrinosis, a lethal autosomal recessive disorder in which the mutant integrin is incapable of switching from the inactive bent to the activated open conformation …”

“…60 A V438M mutation in ITGB6 has been attributed as the cause for β6 integrinosis, a lethal autosomal recessive disorder in which the mutant integrin is incapable of switching from the inactive bent to the activated open conformation. 61 Integrin αvβ6 has a preference for an RGDLXXL/I sequence motif within the pro-domain of TGF-β1 and TGF-β3. X-ray crystallographic investigation by Springer and co-workers elucidated the structural determinants of the integrin β subunit specificity for latent TGF-β.…”

Anti-integrin αvβ6 autoantibodies in patients with primary sclerosing cholangitis

“…Integrin αvβ6 on biliary epithelial cells is important for promoting the proliferation of biliary epithelial cells following liver injuries [ 14 ]. A recent report showed that germline mutations in human integrin β6, a subunit of integrin αvβ6, cause lethal cholestatic liver injuries and bloody diarrhea [ 15 ], which are major symptoms of PSC and UC, respectively, suggesting that integrin αvβ6 is a key molecule for PSC as well as UC.…”

“…Considering the close link between PSC and UC, the report that the human integrin β6 mutation causes PSC- and UC-like clinical characteristics [ 15 ], and the presence of anti-integrin αvβ6 autoantibodies in most patients with UC [ 8 ], we hypothesized that patients with PSC also possess autoantibodies against integrin family proteins, especially integrin αvβ6.…”