Figure 1

Illustration of the proteins cubilin and amnionless mutated in IGS and intrinsic factor mutated in IFD, leading to inherited cobalamin malabsorption. Mutations that cause IGS in cubilin were restricted to exons 1–28 that encode the amnionless binding domain (EGF1-8) and the IF-Cbl binding region (CUB5-8). Two other mutations located towards the carboxy-terminal end (p.Ser2785fs in CUB20 and p.Ile2984Val in CUB22) caused proteinuria. Mutations in amnionless and intrinsic factor were located throughout the protein and many mutations affect splicing (Table 1). The mutational hotspot in AMN includes the transmembrane domain and flanking GC-rich repetitive genomic sequences that are apparently unstable (see text). CUB means complement C1r/C1s, Uegf, and Bone morphogenic protein-1, EGF means epidermal growth factor repeats, IF means intrinsic factor, CR means cysteine-rich domain, SS means signal sequence (aa 1–19), TM means transmembrane domain (aa 360–380), and aa means amino acid. The proteins are not drawn to scale.