Twigg, Stephen R. F. and Hufnagel, Robert B. and Miller, Kerry A. and Zhou, Yan and McGowan, Simon J. and Taylor, John and Craft, Jude and Taylor, Jenny C. and Santoro, Stephanie L. and Huang, Taosheng and Hopkin, Robert J. and Brady, Angela F. and Clayton-Smith, Jill and Clericuzio, Carol L. and Grange, Dorothy K. and Groesser, Leopold and Hafner, Christian and Horn, Denise and Temple, I. Karen and Dobyns, William B. and Curry, Cynthia J. and Jones, Marilyn C. and Wilkie, Andrew O. M. (2016) A Recurrent Mosaic Mutation in SMO, Encoding the Hedgehog Signal Transducer Smoothened, Is the Major Cause of Curry-Jones Syndrome. AMERICAN JOURNAL OF HUMAN GENETICS, 98 (6). pp. 1256-1265. ISSN 0002-9297, 1537-6605
Full text not available from this repository. (Request a copy)Abstract
Curry-Jones syndrome (CJS) is a multisystem disorder characterized by patchy skin lesions, polysyndactyly, diverse cerebral malformations, unicoronal craniosynostosis, iris colobomas, microphthalmia, and intestinal malrotation with myofibromas or hamartomas. Cerebellar medulloblastoma has been described in a single affected individual; in another, biopsy of skin lesions showed features of trichoblastoma. The combination of asymmetric clinical features, patchy skin manifestations, and neoplastic association previously led to the suggestion that this could be a mosaic condition, possibly involving hedgehog (Hh) signaling. Here, we show that CJS is caused by recurrent somatic mosaicism for a nonsynonymous variant in SMO (c.1234C>T [p.Leu412Phe]), encoding smoothened (SMO), a G-protein-coupled receptor that transduces Hh signaling. We identified eight mutation-positive individuals (two of whom had not been reported previously) with highly similar phenotypes and demonstrated varying amounts of the mutant allele in different tissues. We present detailed findings from brain MRI in three mutation-positive individuals. Somatic SMO mutations that result in constitutive activation have been described in several tumors, including medulloblastoma, ameloblastoma, and basal cell carcinoma. Strikingly, the most common of these mutations is the identical nonsynonymous variant encoding p.Leu412Phe. Furthermore, this substitution has been shown to activate SMO in the absence of Hh signaling, providing an explanation for tumor development in CJS. This raises therapeutic possibilities for using recently generated Hh-pathway inhibitors. In summary, our work uncovers the major genetic cause of CJS and illustrates strategies for gene discovery in the context of low-level tissue-specific somatic mosaicism.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | BASAL-CELL CARCINOMA; GENOMIC ANALYSIS; NEVUS SYNDROME; HUMAN HOMOLOG; MEDULLOBLASTOMA; SPECTRUM; RECEPTOR; ABNORMALITIES; MALFORMATIONS; OVERGROWTH; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Dermatologie und Venerologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 22 Mar 2019 08:31 |
| Last Modified: | 22 Mar 2019 08:31 |
| URI: | https://pred.uni-regensburg.de/id/eprint/2785 |
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