Three Mutations of CYLD Gene in Chinese Families With Multiple Familial Trichoepithelioma

Lv, Hongli.*; Li, Cheng*; Li, Yan*; Tang, Jinhui.*; Zhang, Zheng

American Journal of Dermatopathology:
doi: 10.1097/DAD.0b013e318297f825
Letters to the Editor
Author Information

*Department of Dermatology, Jiading Center Hospital, Shanghai, China

Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China

Supported by grants from the Board of Health Jiading District, Shanghai, China (NO.KYXM 2009-12-6).

The authors declare no conflict of interest.

Article Outline

To the Editor:

Multiple familial trichoepithelioma (MFT, OMIM 601606) is an autosomal dominantly inherited disease characterized by numerous skin-colored papules with pilar differentiation. Mutations in the CYLD gene on chromosome 16q12-q13 have been identified as the cause of MFT, familial cylindromatosis, and Brooke–Spiegler syndrome (BSS).1 Herein, we performed mutation detection of the CYLD gene in 3 Chinese families with MFT. We found a novel frameshift mutation (c.2255delT) and 2 recurrent nonsense mutations (c.1112C>A and c.2299A>T), the latter was first reported associated with MFT.

After informed consent, skin biopsies from the index case from family F1 to F3 were collected. Pedigree analysis in these families was consistent with autosomal-dominant inheritance of the disease (Figs. 1A–C). All the probands presented with a relatively mild phenotype: mainly, numerous confluent skin-colored papules and nodules, which measured 2–4 mm in diameter, located primarily over central face, and most prominently along the nasolabial folds and the nose. The scalps of the probands were clear (Figs. 1D–F, Table 1). Histological analysis of tumors revealed typical characteristics of trichoepithelioma: islands of basaloid cells with palisading periphery and small horn cysts (Figs. 1G–I). Blood samples were collected from all available individuals and 100 unrelated population-matched controls. Polymerase chain reaction and sequence analysis were performed as described previously.2

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.

To date, a total of 87 distinct germline CYLD mutations have been reported with diverse ethnic and racial background. Of these mutations, 35% (30) are nonsense/missense, 53% (46) are frameshift, 10% (9) are putative splice site, 1% (1) small indel, and 1% (1) gross deletion.3–5 CYLD mutations have been solely identified in the C-terminal in two-thirds of the gene (exons 9–20), even though exons 4–8 are translated. Totally, 6 missense mutations were reported to occur only within the ubiquitin-specific protease (USP) domain of the CYLD protein, and all of them were associated with MFT.2,6–10

In agreement with all previously identified sequence changes in CYLD, the localization of the abnormalities described in this study was in exons 9–20. In family 1, the deletion [c.2255delT (Leu751fsX774)] was in exon 17 in the 3′ UTR of CYLD if the deletion will lead to a stable messenger RNA, the mutant RNA will encode a protein, which is part of the USP domain (aa 583–956). The USP domain located in C-terminal region is responsible for deubiquitination activity, and the mutant CYLD protein will lack a part of its functional domain; this explains the clinical phenotype of the patient. Addition with our reported mutation in family 2, the c.1112C>A/p.S371X nonsense mutation was the most common mutation previously reported associated with BSS, FC, or MFT. The c.2299A>T mutation was also reported previously associated with BSS, but it was first reported associated with MTF in this study.

In summary, we found a novel frameshift mutation and 2 recurrent CYLD nonsense mutations associated with MFT. Summarized the reported CYLD mutations, the ongoing recognition of mutations and signaling pathway will insight into the unknown mechanism leading to MFT.

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The authors thank the individuals and their families who participated in this project.

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