The University of Southampton
University of Southampton Institutional Repository

A recurrent mosaic mutation of SMO, encoding the hedgehog signal transducer smoothened, is the major cause of Curry-Jones syndrome

A recurrent mosaic mutation of SMO, encoding the hedgehog signal transducer smoothened, is the major cause of Curry-Jones syndrome
A recurrent mosaic mutation of SMO, encoding the hedgehog signal transducer smoothened, is the major cause of Curry-Jones syndrome
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.
0002-9297
1256-1265
Twigg, Stephen R.F.
894d2681-a4c2-4571-825b-72577969617b
Hufnagel, Robert B.
372e28c0-aa21-446b-a19a-4e28fb4924c0
Miller, Kerry A.
5b3b5b04-12c7-45da-8e8a-4277df3c754e
Zhou, Yan
7ffa57ee-d3eb-420c-a5a2-67b2330a0757
McGowan, Simon J.
ff555052-1855-46ee-abc5-6d0783d6b77a
Taylor, John
fbd69808-f1e0-489d-8573-3b22e8f1de82
Craft, Jude
334e320f-4190-4139-9310-c2ff4f989ff2
Taylor, Jenny C.
52b015d8-7a23-45c1-a6aa-80df9c1b873c
Santoro, Stephanie L.
69190287-36e0-4c49-9144-009978546683
Huang, Taosheng
a734fc91-6c1e-4f21-8784-3f269d929866
Hopkin, Robert J.
a1c020e9-5413-4347-9a58-8601b3a202ed
Brady, Angela F.
6a592734-d3ec-40dd-a159-f157cd8f56eb
Clayton-Smith, Jill
df8946ac-9da9-4ef2-b180-f468a5424844
Clericuzio, Carol L.
65cc09e0-f251-4054-a239-81d11dc0ef0e
Grange, Dorothy K.
397e244d-d4b3-46c4-a153-e2b2a40da131
Groesser, Leopold
d703c62d-d9d8-4c26-841e-c596d5757b11
Hafner, Christian
93ec4984-a731-411f-bf52-4966cc080aa5
Horn, Denise
d6a78287-fea8-48e0-ab6b-9bb154358fb1
Temple, I. Karen
d63e7c66-9fb0-46c8-855d-ee2607e6c226
Dobyns, William B.
1859e3ad-3059-4912-8825-e6b76937aeb9
Curry, Cynthia J.
6e21a65e-ca44-4348-acfb-17147937d639
Jones, Marilyn C.
94667cf1-38a6-4ad7-ab74-4af3b3b6c0ea
Wilkie, Andrew O.M.
7064a09e-66d9-4acf-92eb-cffad1ce3762
Twigg, Stephen R.F.
894d2681-a4c2-4571-825b-72577969617b
Hufnagel, Robert B.
372e28c0-aa21-446b-a19a-4e28fb4924c0
Miller, Kerry A.
5b3b5b04-12c7-45da-8e8a-4277df3c754e
Zhou, Yan
7ffa57ee-d3eb-420c-a5a2-67b2330a0757
McGowan, Simon J.
ff555052-1855-46ee-abc5-6d0783d6b77a
Taylor, John
fbd69808-f1e0-489d-8573-3b22e8f1de82
Craft, Jude
334e320f-4190-4139-9310-c2ff4f989ff2
Taylor, Jenny C.
52b015d8-7a23-45c1-a6aa-80df9c1b873c
Santoro, Stephanie L.
69190287-36e0-4c49-9144-009978546683
Huang, Taosheng
a734fc91-6c1e-4f21-8784-3f269d929866
Hopkin, Robert J.
a1c020e9-5413-4347-9a58-8601b3a202ed
Brady, Angela F.
6a592734-d3ec-40dd-a159-f157cd8f56eb
Clayton-Smith, Jill
df8946ac-9da9-4ef2-b180-f468a5424844
Clericuzio, Carol L.
65cc09e0-f251-4054-a239-81d11dc0ef0e
Grange, Dorothy K.
397e244d-d4b3-46c4-a153-e2b2a40da131
Groesser, Leopold
d703c62d-d9d8-4c26-841e-c596d5757b11
Hafner, Christian
93ec4984-a731-411f-bf52-4966cc080aa5
Horn, Denise
d6a78287-fea8-48e0-ab6b-9bb154358fb1
Temple, I. Karen
d63e7c66-9fb0-46c8-855d-ee2607e6c226
Dobyns, William B.
1859e3ad-3059-4912-8825-e6b76937aeb9
Curry, Cynthia J.
6e21a65e-ca44-4348-acfb-17147937d639
Jones, Marilyn C.
94667cf1-38a6-4ad7-ab74-4af3b3b6c0ea
Wilkie, Andrew O.M.
7064a09e-66d9-4acf-92eb-cffad1ce3762

Twigg, Stephen R.F., Hufnagel, Robert B., Miller, Kerry A., Zhou, Yan, McGowan, Simon J., Taylor, John, Craft, Jude, Taylor, Jenny C., Santoro, Stephanie L., Huang, Taosheng, Hopkin, Robert J., Brady, Angela F., Clayton-Smith, Jill, Clericuzio, Carol L., Grange, Dorothy K., Groesser, Leopold, Hafner, Christian, Horn, Denise, Temple, I. Karen, Dobyns, William B., Curry, Cynthia J., Jones, Marilyn C. and Wilkie, Andrew O.M. (2016) A recurrent mosaic mutation of SMO, encoding the hedgehog signal transducer smoothened, is the major cause of Curry-Jones syndrome. The American Journal of Human Genetics, 98 (6), 1256-1265. (doi:10.1016/j.ajhg.2016.04.007). (PMID:27236920)

Record type: Article

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.

Text
__userfiles.soton.ac.uk_Users_nl2_mydesktop_Deposits_One off_CJS paper vs4AW.docx - Accepted Manuscript
Download (165kB)
Other
1-s2.0-S0002929716301021-main.pdf__tid=e88d1dce-9b83-11e6-8615-00000aab0f27&acdnat=1477490332_d38192f7955d116c4dbff2cb24b51b7b - Version of Record
Download (1MB)

More information

Accepted/In Press date: 27 April 2016
e-pub ahead of print date: 26 May 2016
Published date: 2 June 2016
Organisations: Human Development & Health

Identifiers

Local EPrints ID: 393812
URI: http://eprints.soton.ac.uk/id/eprint/393812
ISSN: 0002-9297
PURE UUID: eaad49c0-389b-4e74-b56a-c33f0c680ed7
ORCID for I. Karen Temple: ORCID iD orcid.org/0000-0002-6045-1781

Catalogue record

Date deposited: 06 May 2016 08:49
Last modified: 07 Oct 2020 06:03

Export record

Altmetrics

Contributors

Author: Stephen R.F. Twigg
Author: Robert B. Hufnagel
Author: Kerry A. Miller
Author: Yan Zhou
Author: Simon J. McGowan
Author: John Taylor
Author: Jude Craft
Author: Jenny C. Taylor
Author: Stephanie L. Santoro
Author: Taosheng Huang
Author: Robert J. Hopkin
Author: Angela F. Brady
Author: Jill Clayton-Smith
Author: Carol L. Clericuzio
Author: Dorothy K. Grange
Author: Leopold Groesser
Author: Christian Hafner
Author: Denise Horn
Author: I. Karen Temple ORCID iD
Author: William B. Dobyns
Author: Cynthia J. Curry
Author: Marilyn C. Jones
Author: Andrew O.M. Wilkie

University divisions

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×