title: A Recurrent Mosaic Mutation in SMO, Encoding the Hedgehog Signal Transducer Smoothened, Is the Major Cause of Curry-Jones Syndrome.
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.
authors.affiliation: Clinical Genetics Group, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
authors.forename: Stephen R F
authors.initials: SRF
authors.lastname: Twigg
authors.affiliation: Division of Human Genetics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, MLC 4006, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Hufnagel
authors.affiliation: Clinical Genetics Group, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
authors.forename: Kerry A
authors.initials: KA
authors.lastname: Miller
authors.affiliation: Clinical Genetics Group, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Computational Biology Research Group, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: McGowan
authors.affiliation: Wellcome Trust Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford OX3 7BN, UK; Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Churchill Hospital, Oxford OX3 7LE, UK.
authors.forename: John
authors.initials: J
authors.lastname: Taylor
authors.affiliation: Wellcome Trust Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford OX3 7BN, UK.
authors.forename: Jude
authors.initials: J
authors.lastname: Craft
authors.affiliation: Wellcome Trust Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford OX3 7BN, UK; Oxford Biomedical Research Centre, National Institute for Health Research, Oxford OX3 7BN, UK.
authors.forename: Jenny C
authors.initials: JC
authors.lastname: Taylor
authors.affiliation: Division of Human Genetics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, MLC 4006, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Santoro
authors.affiliation: Division of Human Genetics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, MLC 4006, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
authors.forename: Taosheng
authors.initials: T
authors.lastname: Huang
authors.affiliation: Division of Human Genetics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, MLC 4006, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Hopkin
authors.affiliation: North West Thames Regional Genetics Service, Kennedy-Galton Centre, Northwick Park Hospital, Harrow HA1 3UJ, UK.
authors.forename: Angela F
authors.initials: AF
authors.lastname: Brady
authors.affiliation: Manchester Centre for Genomic Medicine, St. Mary's Hospital, University of Manchester, Manchester M13 9WL, UK.
authors.forename: Jill
authors.initials: J
authors.lastname: Clayton-Smith
authors.affiliation: Division of Genetics/Dysmorphology, Department of Pediatrics, University of New Mexico, Albuquerque, NM 87131, USA.
authors.forename: Carol L
authors.initials: CL
authors.lastname: Clericuzio
authors.affiliation: Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Dorothy K
authors.initials: DK
authors.lastname: Grange
authors.affiliation: Department of Dermatology, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Leopold
authors.initials: L
authors.lastname: Groesser
authors.affiliation: Department of Dermatology, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Hafner
authors.affiliation: Institute for Medical Genetics and Human Genetics, Charité Universitätsmedizin Berlin, 13353 Berlin, Germany.
authors.forename: Denise
authors.initials: D
authors.lastname: Horn
authors.affiliation: Human Development and Health, Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, UK; Wessex Clinical Genetics Service, Princess Anne Hospital, University Hospital Southampton NHS Foundation Trust, Southampton SO16 6YD, UK.
authors.forename: I Karen
authors.initials: IK
authors.lastname: Temple
authors.affiliation: Center for Integrative Brain Research, Seattle Children's Hospital, Seattle, WA 98105, USA.
authors.forename: William B
authors.initials: WB
authors.lastname: Dobyns
authors.affiliation: Genetic Medicine, University of California, San Francisco, Fresno, CA 93701, USA.
authors.forename: Cynthia J
authors.initials: CJ
authors.lastname: Curry
authors.affiliation: Department of Pediatrics, University of California, San Diego, and Rady Children's Hospital, San Diego, CA 92123, USA.
authors.forename: Marilyn C
authors.initials: MC
authors.lastname: Jones
authors.affiliation: Clinical Genetics Group, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK. Electronic address: andrew.wilkie@imm.ox.ac.uk.
authors.forename: Andrew O M
authors.initials: AOM
authors.lastname: Wilkie
mesh_terms: D002675:Child, Preschool; D019465:Craniofacial Abnormalities / Q000209:etiology* / Q000473:pathology; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007422:Intestines / Q000002:abnormalities* / Q000473:pathology; D008297:Male; D009154:Mutation / Q000235:genetics*; D015398:Signal Transduction; D012868:Skin Abnormalities / Q000209:etiology* / Q000473:pathology; D000072086:Smoothened Receptor / Q000235:genetics*; D013576:Syndactyly / Q000209:etiology* / Q000473:pathology
chemical_list: C491023:SMO protein, human; D000072086:Smoothened Receptor