Sequence analysis revealed a frameshift mutation in family 1 and family 2 nonsense mutations in family 2 and family 3 (Fig. 2). In family 1, the novel frameshift mutation c.2255delT (Leu751fsX774) was detected in exon 17 of the CYLD gene. The mutation changed the reading frame after codon 751, resulting in a premature stop signal at codon 774. The gene with the frameshift mutation would make the truncated protein, which lost the Cys-X-X-Cys pairs [between amino acid (aa) 788 and 856] and the catalytic domain of ubiquitin carboxyl-terminal hydrolases type 2 (UCH2-2, aa 871–889). In family 2, the nonsense mutation c.1112C>A (p.S371X) was detected in exon 9, generating a premature stop signal at coding 371 before a cytoskeleton-associated protein–glycine conserved (CAP-Gly, aa 472–540), proline-rich repeat (aa 388–413 and 446–471), Cys-X-X-Cys pairs, and UCH2 (aa 593–610 and 871–889). In family 3, DNA sequencing revealed an A-to-T transition in exon 17 (c.2299A>T), generating a premature stop signal at coding 767 before Cys-X-X-Cys pairs and the UCH2-2 domain. The mutations were found in all patients but not in the healthy members of each family and 100 unrelated controls expect family 2. In family 2, individual 23 (Fig. 1B) was a carrier of the mutation (c.1112C>A); he has not yet shown any lesion at the age of 9. Thus, we successfully made a genetic diagnosis. The results of clinical features and CYLD mutations in 3 MFT families are summarized in Table 1.
The authors thank the individuals and their families who participated in this project.
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