(A) Structure of TANGO1 protein. The lumenal portion contains an N-terminal signal sequence followed by an SH3-like domain required for cargo binding, as well as a coiled-coil domain. A trans- and intramembrane domain anchors TANGO1 within the ER membrane. The cytoplasmic portion consists of two coiled-coil domains (CC1, also named TEER, and CC2) and a proline-rich domain at the C-terminus. The identified mutation affects residue 1207 (p.(Arg1207=)) between the intramembrane and the CC1 domain at the beginning of the cytoplasmic portion. (B) Pedigree of the studied family. Filled or clear symbols represent affected or unaffected individuals, respectively. The parents (I.1 and I.2) are first cousins. The four affected sons (II.1, II.2, II.4, and II.5) share a homozygous TANGO1 (c.3621A > G) variant. The healthy child II.3 died in a household accident at the age of 16. (C) Dental and skeletal abnormalities of the affected brothers II.2, II.4, and II.5. Note the brachydactyly of hands and feet, clinodactyly of the fifth finger, dentinogenesis imperfecta (including an opalescent tooth discoloration with severe attrition affecting the primary and permanent dentition, as well as juvenile periodontitis, bulbous crowns, long and tapered roots, and obliteration of the pulp chamber and canals in the permanent dentition), the skin lesions due to pruritus in all affected children; and the scoliosis in II.4 and II.5.