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.
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We are grateful to all the families for their participation in this study. We thank the staff at the high-throughput genomics facility at the Wellcome Trust Centre for Human Genetics (Oxford Genomics Centre) for exome sequencing and Sue Butler, John Frankland, and Tim Rostron for help with cell culture and DNA sequencing. This work was supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre Programme (J.C.T. and A.O.M.W.), the Medical Research Council through the Weatherall Institute of Molecular Medicine Strategic Alliance (G0902418 and MC_UU_12025), and the Wellcome Trust (project grant 093329 to A.O.M.W. and S.R.F.T. and Senior Investigator Award 102731 to A.O.M.W.). The views expressed in this publication are those of the authors and not necessarily those of the National Health Service, NIHR, or Department of Health.