Novel LBR pathogenic variants with loss of sterol reductase activity participate in the pathogenesis of skeletal dysplasia via dysregulating canonical Wnt pathway

Abstract

Biallelic pathogenic variants in the lamin B receptor (LBR) with impaired sterol reductase function are associated with the development of perinatal lethal Greenberg dysplasia (GRBGD) and mild nonfatal skeletal dysplasia with or without Pelger-Huet anomaly (PHASK), as well as other related hereditary skeletal dysplasia. However, the underlying molecular mechanism remains unclear. In this study, we found two novel pathogenic variants of LBR, namely missense mutation (c.1011 T > G, NM_002296.4; p.Cys337Trp, NP_002287.2) and LBR gene deletion (Chr1q42.12 (225,515,082-225,633,464), NC_000001.10). LBR is a novel substrate of FBW7, which is degraded by GSK3β/FBW7-mediated proteasome pathway and whose C337W mutation promotes its degradation through enhanced interaction with FBW7. Wild-type but not C337W mutant LBR is upregulated by WNT3A-mediated inactivation of GSK3β/FBW7 axis and then participated in WNT3A-activated Wnt pathway through its mediated cholesterol synthesis. MC3T3-E1 cells with Lbr knockdown or cholesterol removal exhibited reduced mineralized nodules in the presence of WNT3A, but addition of cholesterol in the culture medium reversed this phenotype. Collectively, we detected two novel variants in LBR and our study revealed for the first time that disruption of cholesterol synthesis by LBR impairs Wnt pathway and thus disrupts the cell osteogenic differentiation, providing new insights into the pathogenesis of skeletal dysplasia caused by LBR variation.