Investigating the Effects of a Novel Fibronectin Mutation: The Role of ER Stress and Collagen Fibrillogenesis in the Pathogenesis of Spondylometaphyseal Dysplasia

Abstract

Spondylometaphyseal dysplasia (SMD) is a group of skeletal disorders characterized by deformities of the spine and long bones. While the etiology of many SMDs are unknown, the discovery of a novel fibronectin mutation (FNC97W) has been recently linked to an individual with SMD. Fibronectin (FN) is a vital extracellular matrix (ECM) protein that assembles into a fibrillar matrix and regulates cellular activities, including matrix assembly of other ECM proteins such as type I collagen (COL1). Proper assembly of the ECM is essential for normal cell and tissue development, providing organization, developmental signals, and structural support to cells. Mutations in COL1 and other ECM proteins have been linked to skeletal disease through a number of different mechanisms, including deregulated matrix assembly and perturbations in cellular function caused by protein misfolding and subsequent ER stress, suggesting pathways by which our novel FN mutation may lead to SMD. Analyses of primary dermal fibroblasts heterozygous for the FNC97W mutation reveal abnormal accumulation of FN within the ER of the cells, which suggests ER stress and activation of the unfolded protein response (UPR), as well as lower levels of FN in the culture medium, revealing a defect in FN secretion. The cells also assemble a reduced FN matrix and fail to assemble a COL1 matrix. These results provide new insights into the effects of a FN mutation on cellular function, highlighting the importance of FN and COL1 matrix assembly in skeletal development and elucidating their potential role in the pathogenesis of SMD.