F-box proteins have been shown to be critical for the ubiquitin-mediated degradation of cellular regulatory proteins, and they are a family of eukaryotic proteins characterized by an approximately 40 amino acid motif. SCF complex, a class of ubiquitin ligases, consists of invariable components, Skp1 and Cullin, and variable components of F-box proteins, which have a primary role in determining substrate specificity. FBXW4, also known as SHFM3, encodes F-box and WD-40 domain-containing protein 4. Defects in SHFM3 are a cause of split-hand/foot malformation type 3 (SHFM3), an autosomal dominant disorder characterized by hypoplasia/aplasia of the central digits with fusion of the remaining digits.