Fig. 1

a Family pedigree. The proband is indicated by an arrow (P). The segregation was validated by Sanger Sequencing in the main family. b ISG15 consists of two ubl domains (blue) that are linked by a proline residue. ISG15 is synthesized as a 17-kDa precursor that is proteolytically processed into a mature form of 15 kDa. This processing exposes a carboxy-terminal LRLRGG motif, required for ISGylation (yellow). The c.285delC variant produces a frameshift after Threonine 95 which results in a stop codon downstream. The c.299_312del produces a frameshift after Leucine 100 that has no stop codon within the sequence of the original gene. c Crystallographic structure of human ISG15. The area disabled by the mutations is marked in green. Thr95 marks the beginning of the 285_del frameshift. Leu100 marks the beginning of the 299_312del frameshift. The C-terminus of the structure corresponds to the first 3 residues of the conjugation domain. d Partial sequence chromatograms for ISG15 in the patient. DNA sequences of the WT (wild-type) and mutant ISG15 alleles are shown. Red rectangle denotes the sites of heterozygous sequence deletions