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.

Hypomorphic Recessive Variants in SUFU Impair the Sonic Hedgehog Pathway and Cause Joubert Syndrome with Cranio-facial and Skeletal Defects

“…Of note, subjects with CJS also present similar cranio-facial dysmorphisms and polysyndactyly, as well as a spectrum of cerebral malformations including mild cerebellar hypoplasia, corpus callosum abnormalities, and polymicrogyria. 23 Moreover, a proportion of subjects with Gorlin syndrome, caused by heterozygous loss-of-function variants of either PTCH1 or SUFU, variably exhibit macrocephaly, hypertelorism, depressed nasal bridge, post-axial polydactyly, as well as macrosomia and dyskeratotic plantar pits (present in family COR369). 24 These observations suggest that these peculiar cranio-facial and digit anomalies are strictly related to abnormal activation of the SHH pathway, caused either by reduced levels (or functioning) of repressor proteins or by the constitutive activation of proteins that transduce SHH signaling.…”

“…[16][17][18][19] Similarly, heterozygous pathogenic variants directly affecting several members of the SHH pathway, including SHH itself (MIM: 600725), PTCH1, SMO (MIM: 601500), GLI2 (MIM: 165230), or GLI3 (MIM: 165240), result in a spectrum of autosomal-dominant developmental disorders including holoprosencephaly (MIM: 142945), schizencephaly with polymicrogyria (MIM: 269160), Curry-Jones syndrome (CJS [MIM: 601707]), Greig cephalopolysyndactyly syndrome (GCPS [MIM: 175700]), Pallister-Hall syndrome (MIM: 146510), and non-syndromic polydactylies (MIM: 174200, 174700), that are variably characterized by anomalies of the brain, midline face, and/or limbs. [20][21][22][23] An aberrant activity of the SHH pathway has also been firmly associated with increased risk of developing cancer. Germline heterozygous loss-of-function variants of either PTCH1 or SUFU (MIM: 607035) may cause a complex condition termed nevoid-basal-cell carcinoma syndrome (Gorlin syndrome [MIM: 109400]), characterized by the occurrence of several basal cell carcinomas and other cancers at a young age (<20 years), variably associated with developmental and skeletal abnormalities.…”

Genetic Causes of Craniosynostosis: An Update

“…In 8 patients with phenotypical features of CurryJones syndrome (OMIM 601707), recurrent somatic mosaicism was identified for a nonsynonymous variant in SMO , p.(Leu412Phe) [Twigg et al, 2016].…”

“…SMO encodes a frizzled G-protein-coupled receptor that plays a key role in transduction of Hedgehog signaling [Twigg et al, 2016]. The aforementioned substitution has been shown to constitutively activate SMO in the absence of Hedgehog signaling [Sweeney et al, 2014;Atwood et al, 2015].…”

“…Curry-Jones syndrome comprises patchy skin lesions (including streaky skin lesions, nevus sebaceous, and trichoblastoma), polysyndactyly, diverse cerebral malformations (including medulloblastoma), unicoronal synostosis, iris colobomas, microphthalmia, and intestinal malrotation with myofibromas or hamartomas [Twigg et al, 2016]. SMO encodes a frizzled G-protein-coupled receptor that plays a key role in transduction of Hedgehog signaling [Twigg et al, 2016].…”