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Intronic splicing mutations in PTCH1 cause Gorlin syndrome

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Abstract

Gorlin syndrome is an autosomal dominant disorder characterized by multiple early-onset basal cell carcinoma, odontogenic keratocysts and skeletal abnormalities. It is caused by heterozygous mutations in the tumour suppressor PTCH1. Routine clinical genetic testing, by Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA) to confirm a clinical diagnosis of Gorlin syndrome, identifies a mutation in 60–90 % of cases. We undertook RNA analysis on lymphocytes from ten individuals diagnosed with Gorlin syndrome, but without known PTCH1 mutations by exonic sequencing or MLPA. Two altered PTCH1 transcripts were identified. Genomic DNA sequence analysis identified an intron 7 mutation c.1068-10T>A, which created a strong cryptic splice acceptor site, leading to an intronic insertion of eight bases; this is predicted to create a frameshift p.(His358Alafs*12). Secondly, a deep intronic mutation c.2561-2057A>G caused an inframe insertion of 78 intronic bases in the cDNA transcript, leading to a premature stop codon p.(Gly854fs*3). The mutations are predicted to cause loss of function of PTCH1, consistent with its tumour suppressor function. The findings indicate the importance of RNA analysis to detect intronic mutations in PTCH1 not identified by routine screening techniques.

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Acknowledgments

The authors wish to thank the individuals who participated in the study, the British Skin Foundation for funding and the Manchester Biomedical Research Centre for hosting the work. DGE is an NIHR Senior Investigator.

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Authors and Affiliations

  1. Manchester Centre for Genomic Medicine, University of Manchester, Manchester, M13 9WL, UK

    Zaynab Bholah, Miriam J. Smith, Helen J. Byers, Emma K. Miles, D. Gareth Evans & William G. Newman

  2. Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester, M13 9WL, UK

    Zaynab Bholah, Miriam J. Smith, Helen J. Byers, Emma K. Miles, D. Gareth Evans & William G. Newman

  3. Manchester Centre for Genomic Medicine, St Mary’s Hospital, Manchester, M13 9WL, UK

    D. Gareth Evans & William G. Newman

Authors
  1. Zaynab Bholah
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  2. Miriam J. Smith
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  3. Helen J. Byers
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  4. Emma K. Miles
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  5. D. Gareth Evans
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  6. William G. Newman
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Corresponding authors

Correspondence to D. Gareth Evans or William G. Newman.

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D. Gareth Evans and William G. Newman have contributed equally to the study.

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Bholah, Z., Smith, M.J., Byers, H.J. et al. Intronic splicing mutations in PTCH1 cause Gorlin syndrome. Familial Cancer 13, 477–480 (2014). https://doi.org/10.1007/s10689-014-9712-9

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  • DOI: https://doi.org/10.1007/s10689-014-9712-9

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