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Nevoid basal cell carcinoma syndrome caused by splicing mutations in the PTCH1 gene

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Abstract

Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by developmental defects and tumorigenesis such as medulloblastomas and basal cell carcinomas, caused by mutations of the patched-1 (PTCH1) gene. To date, we have detected 73 mutations in PTCH1 and ten of them (14 %) were suspected splicing mutations. Eight out of the ten mutations were localized near the splice donor site. Five mutations were localized within the invariant GT-AG splice site, whereas the other five mutations occurred outside the invariant GT-AG site including the last exonic nucleotide. When the transcripts were examined, all mutations resulted in aberrant splicing, including exon skipping or the activation of cryptic splice sites. This is the first extensive report of NBCCS focusing on splice site mutations, and it highlights the importance of analyzing transcripts especially for mutations lying outside the GT-AG splicing consensus site. In addition, the splice site score calculated by Splice-Site Analyzer Tool provided by Tel Aviv University helped predict aberrant splice patterns in most of the cases.

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References

  1. Gorlin RJ (1987) Nevoid basal-cell carcinoma syndrome. Med (Baltim) 66:98–113

    Article  CAS  Google Scholar 

  2. Evans DG, Howard E, Giblin C, Clancy T, Spencer H, Huson SM (2010) Birth incidence and prevalence of tumor-prone syndromes: estimates from a UK family genetic register service. Am J Med Genet A 152A:327–332

    Article  CAS  PubMed  Google Scholar 

  3. Shanley S, Ratcliffe J, Hockey A, Haan E, Oley C, Ravine D, Martin N, Wicking C, Chenevix-Trench G (1994) Nevoid basal cell carcinoma syndrome: review of 118 affected individuals. Am J Med Genet 50:282–290

    Article  CAS  PubMed  Google Scholar 

  4. Endo M, Fujii K, Sugita K, Saito K, Kohno Y, Miyashita T (2012) Nationwide survey of nevoid basal cell carcinoma syndrome in Japan revealing the low frequency of basal cell carcinoma. Am J Med Genet A 158A:351–357

    Article  PubMed  Google Scholar 

  5. Fujii K, Ohashi H, Suzuki M, Hatsuse H, Shiohama T, Uchikawa H, Miyashita T (2013) Frameshift mutation in the PTCH2 gene can cause nevoid basal cell carcinoma syndrome. Fam Cancer 12:611–614

    Article  PubMed  Google Scholar 

  6. Kijima C, Miyashita T, Suzuki M, Oka H, Fujii K (2012) Two cases of nevoid basal cell carcinoma syndrome associated with meningioma caused by a PTCH1 or SUFU germline mutation. Fam Cancer 11:565–570

    Article  PubMed  Google Scholar 

  7. Smith MJ, Beetz C, Williams SG, Bhaskar SS, O’Sullivan J, Anderson B, Daly SB, Urquhart JE, Bholah Z, Oudit D, Cheesman E, Kelsey A, McCabe MG, Newman WG, Evans DG (2014) Germline mutations in SUFU cause Gorlin syndrome-associated childhood medulloblastoma and redefine the risk associated with PTCH1 mutations. J Clin Oncol 32:4155–4161

    Article  CAS  PubMed  Google Scholar 

  8. Johnson RL, Rothman AL, Xie J, Goodrich LV, Bare JW, Bonifas JM, Quinn AG, Myers RM, Cox DR, Epstein EH Jr, Scott MP (1996) Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science 272:1668–1671

    Article  CAS  PubMed  Google Scholar 

  9. Hahn H, Wicking C, Zaphiropoulous PG, Gailani MR, Shanley S, Chidambaram A, Vorechovsky I, Holmberg E, Unden AB, Gillies S, Negus K, Smyth I, Pressman C, Leffell DJ, Gerrard B, Goldstein AM, Dean M, Toftgard R, Chenevix-Trench G, Wainwright B, Bale AE (1996) Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell 85:841–851

    Article  CAS  PubMed  Google Scholar 

  10. Ingham PW, McMahon AP (2001) Hedgehog signaling in animal development: paradigms and principles. Genes Dev 15:3059–3087

    Article  CAS  PubMed  Google Scholar 

  11. Krawczak M, Reiss J, Cooper DN (1992) The mutational spectrum of single base-pair substitutions in mRNA splice junctions of human genes: causes and consequences. Hum Genet 90:41–54

    Article  CAS  PubMed  Google Scholar 

  12. Bholah Z, Smith MJ, Byers HJ, Miles EK, Evans DG, Newman WG (2014) Intronic splicing mutations in PTCH1 cause Gorlin syndrome. Fam Cancer 13:477–480

    Article  CAS  PubMed  Google Scholar 

  13. Kimonis VE, Goldstein AM, Pastakia B, Yang ML, Kase R, DiGiovanna JJ, Bale AE, Bale SJ (1997) Clinical manifestations in 105 persons with nevoid basal cell carcinoma syndrome. Am J Med Genet 69:299–308

    Article  CAS  PubMed  Google Scholar 

  14. Suzuki M, Nagao K, Hatsuse H, Sasaki R, Saito K, Fujii K, Miyashita T (2013) Molecular pathogenesis of keratocystic odontogenic tumors developing in nevoid basal cell carcinoma syndrome. Oral Surg Oral Med Oral Pathol Oral Radiol 116:348–353

    Article  PubMed  Google Scholar 

  15. Maquat LE (2002) Nonsense-mediated mRNA decay. Curr Biol 12:R196–R197

    Article  CAS  PubMed  Google Scholar 

  16. Shapiro MB, Senapathy P (1987) RNA splice junctions of different classes of eukaryotes: sequence statistics and functional implications in gene expression. Nucleic Acids Res 15:7155–7174

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Carmel I, Tal S, Vig I, Ast G (2004) Comparative analysis detects dependencies among the 5′ splice-site positions. RNA 10:828–840

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Wicking C, Shanley S, Smyth I, Gillies S, Negus K, Graham S, Suthers G, Haites N, Edwards M, Wainwright B, Chenevix-Trench G (1997) Most germ-line mutations in the nevoid basal cell carcinoma syndrome lead to a premature termination of the PATCHED protein, and no genotype-phenotype correlations are evident. Am J Hum Genet 60:21–26

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Burset M, Seledtsov IA, Solovyev VV (2001) SpliceDB: database of canonical and non-canonical mammalian splice sites. Nucleic Acids Res 29:255–259

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Teraoka SN, Telatar M, Becker-Catania S, Liang T, Onengut S, Tolun A, Chessa L, Sanal O, Bernatowska E, Gatti RA, Concannon P (1999) Splicing defects in the ataxia-telangiectasia gene, ATM: underlying mutations and consequences. Am J Hum Genet 64:1617–1631

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Nozu K, Vorechovsky I, Kaito H, Fu XJ, Nakanishi K, Hashimura Y, Hashimoto F, Kamei K, Ito S, Kaku Y, Imasawa T, Ushijima K, Shimizu J, Makita Y, Konomoto T, Yoshikawa N, Iijima K (2014) X-linked Alport syndrome caused by splicing mutations in COL4A5. Clin J Am Soc Nephrol 9:1958–1964

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Dong J, Gailani MR, Pomeroy SL, Reardon D, Bale AE (2000) Identification of PATCHED mutations in medulloblastomas by direct sequencing. Hum Mutat 16:89–90

    Article  CAS  PubMed  Google Scholar 

  23. Pastorino L, Cusano R, Nasti S, Faravelli F, Forzano F, Baldo C, Barile M, Gliori S, Muggianu M, Ghigliotti G, Lacaita MG, Lo Muzio L, Bianchi-Scarra G (2005) Molecular characterization of Italian nevoid basal cell carcinoma syndrome patients. Hum Mutat 25:322–323

    Article  CAS  PubMed  Google Scholar 

  24. Smyth I, Wicking C, Wainwright B, Chenevix-Trench G (1998) The effects of splice site mutations in patients with naevoid basal cell carcinoma syndrome. Hum Genet 102:598–601

    Article  CAS  PubMed  Google Scholar 

  25. Evans DG, Bowers N, Burkitt-Wright E, Miles E, Garg S, Scott-Kitching V, Penman-Splitt M, Dobbie A, Howard E, Ealing J, Vassalo G, Wallace AJ, Newman W, Northern UK, Huson SM, NF1 Research Network (2016) Comprehensive RNA analysis of the NF1 gene in classically affected NF1 affected individuals meeting NIH criteria has high sensitivity and mutation negative testing is reassuring in isolated cases with pigmentary features only. EBioMedicine 7:212–220

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Wappenschmidt B, Becker AA, Hauke J, Weber U, Engert S, Köhler J, Kast K, Arnold N, Rhiem K, Hahnen E, Meindl A, Schmutzler RK (2012) Analysis of 30 putative BRCA1 splicing mutations in hereditary breast and ovarian cancer families identifies exonic splice site mutations that escape in silico prediction. PLoS ONE 7:e50800

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Cartegni L, Chew SL, Krainer AR (2002) Listening to silence and understanding nonsense: exonic mutations that affect splicing. Nat Rev Genet 3:285–298

    Article  CAS  PubMed  Google Scholar 

  28. Uchikawa H, Fujii K, Kohno Y, Katsumata N, Nagao K, Yamada M, Miyashita T (2007) U7 snRNA-mediated correction of aberrant splicing caused by activation of cryptic splice sites. J Hum Genet 52:891–897

    Article  CAS  PubMed  Google Scholar 

  29. Du L, Pollard JM, Gatti RA (2007) Correction of prototypic ATM splicing mutations and aberrant ATM function with antisense morpholino oligonucleotides. Proc Natl Acad Sci USA 104:6007–6012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Taniguchi-Ikeda M, Kobayashi K, Kanagawa M, Yu CC, Mori K, Oda T, Kuga A, Kurahashi H, Akman HO, DiMauro S, Kaji R, Yokota T, Takeda S, Toda T (2011) Pathogenic exon-trapping by SVA retrotransposon and rescue in Fukuyama muscular dystrophy. Nature 478:127–131

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

The authors acknowledge the cooperation of the attending physicians in this study. This study was supported by Ministry of Education, Culture, Sports, Science and Technology of Japan Grant-in-Aid for Scientific Research (KAKENHI) 26461530 (to T. M.), 15K19041 (to K. N.) and 16K09960 (Katsunori Fujii) and by a grant from Kitasato University Graduate School of Medical Sciences (Integrative Research Program 2015–2016) (to T. M.).

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Authors and Affiliations

  1. Department of Molecular Genetics, Kitasato University Graduate School of Medical Sciences, Sagamihara, Japan

    Chise Kato, Yuto Arai, Kazuaki Nagao, Yoshinaga Takayama, Kouzou Kameyama & Toshiyuki Miyashita

  2. Department of Molecular Genetics, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, 252-0374, Japan

    Kentaro Fujii, Hiromi Hatsuse, Kazuaki Nagao, Yoshinaga Takayama, Kouzou Kameyama & Toshiyuki Miyashita

  3. Department of Pediatrics, Chiba University Graduate School of Medicine, Chiba, Japan

    Katsunori Fujii

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  1. Chise Kato
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  2. Kentaro Fujii
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  3. Yuto Arai
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  8. Katsunori Fujii
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  9. Toshiyuki Miyashita
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Correspondence to Toshiyuki Miyashita.

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Kato, C., Fujii, K., Arai, Y. et al. Nevoid basal cell carcinoma syndrome caused by splicing mutations in the PTCH1 gene. Familial Cancer 16, 131–138 (2017). https://doi.org/10.1007/s10689-016-9924-2

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  • DOI: https://doi.org/10.1007/s10689-016-9924-2

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