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Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair

Nature Genetics volume 41, pages 1022–1026 (2009)Cite this article

Abstract

N-myristoylation is a common form of co-translational protein fatty acylation resulting from the attachment of myristate to a required N-terminal glycine residue1,2. We show that aberrantly acquired N-myristoylation of SHOC2, a leucine-rich repeat–containing protein that positively modulates RAS-MAPK signal flow3,4,5,6, underlies a clinically distinctive condition of the neuro-cardio-facial-cutaneous disorders family. Twenty-five subjects with a relatively consistent phenotype previously termed Noonan-like syndrome with loose anagen hair (MIM607721)7 shared the 4A>G missense change in SHOC2 (producing an S2G amino acid substitution) that introduces an N-myristoylation site, resulting in aberrant targeting of SHOC2 to the plasma membrane and impaired translocation to the nucleus upon growth factor stimulation. Expression of SHOC2S2G in vitro enhanced MAPK activation in a cell type–specific fashion. Induction of SHOC2S2G in Caenorhabditis elegans engendered protruding vulva, a neomorphic phenotype previously associated with aberrant signaling. These results document the first example of an acquired N-terminal lipid modification of a protein causing human disease.

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Figure 1: The germline 4A>G mutation in the SHOC2 gene causes a distinctive phenotype of the neuro-cardio-facial-cutaneous syndrome family.
Figure 2: The disease-causing 4A>G change in SHOC2 promotes protein myristoylation and cell membrane targeting.
Figure 3: Functional characterization of the disease-causing 4A>G change in SHOC2.
Figure 4: Consequences of SHOC2S2G expression in C. elegans vulva development.

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NCBI Reference Sequence

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Acknowledgements

We are indebted to the affected individuals and families who participated in the study, the physicians who referred the subjects, A. Fire (Stanford University School of Medicine, Stanford, California) and J.D. McGhee (University of Calgary, Calgary, Canada) for plasmids, and C. Ramoni, S. Venanzi and T. Squatriti (Istituto Superiore di Sanità, Rome, Italy) and the Open Laboratory (IGB-CNR, Naples, Italy) for experimental support. Some nematode strains used in this work were provided by the Caenorhabditis Genetics Center (University of Minnesota, Minneapolis, Minnesota), funded by the US National Institutes of Health (NIH) National Center for Research Resources. We also thank M.C. Silengo (Università di Torino, Turin, Italy), S. Spranger (Praxis fuer Humangenetik, Bremen, Germany), I.M. Gaspar (Egas Moniz Hospital, Lisbon, Portugal) and D.R. Bertola (HC/FMUSP, Saão Paulo, Brazil) for their contribution in DNA sampling and valuable clinical assistance. This research was funded by grants from Telethon-Italy (GGP07115) and 'Convenzione Italia-USA-malattie rare' to M.T., the NIH (HL71207, HD01294 and HL074728) to B.D.G., SBCNY (P50GM071558) to A.M. and R.I. the German Research Foundation (DFG) (ZE 524/4-1) to M.Z. and IRCCS-CSS (Ricerca Corrente 2009) to F.L.

Author information

Author notes

  1. Bruce D Gelb and Marco Tartaglia: These authors contributed equally to this work.

Authors and Affiliations

  1. Dipartimento di Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, Rome, Italy

    Viviana Cordeddu, Valentina Fodale, Simone Martinelli, Elisabetta Flex & Marco Tartaglia

  2. Istituto di Genetica e Biofisica 'A. Buzzati Traverso', Consiglio Nazionale delle Ricerche, Naples, Italy

    Elia Di Schiavi & Paolo Bazzicalupo

  3. Genomics Division, Lawrence Berkeley National Laboratory, Berkeley, California, USA

    Len A Pennacchio

  4. US Department of Energy Joint Genome Institute, Walnut Creek, California, USA

    Len A Pennacchio, Joel Martin, Wendy Schackwitz & Anna Lipzen

  5. Department of Pharmacology and Systems Therapeutics, Systems Biology Center New York (SBCNY), Mount Sinai School of Medicine, New York, New York, USA

    Avi Ma'ayan & Ravi Iyengar

  6. Istituto di Ricovero e Cura a Carattere Scientifico-Casa Sollievo della Sofferenza, San Giovanni Rotondo and Istituto Mendel, Rome, Italy

    Anna Sarkozy, Francesca Lepri & Bruno Dallapiccola

  7. Department of Experimental Medicine, University 'La Sapienza', Rome, Italy

    Valentina Fodale & Bruno Dallapiccola

  8. Dipartimento di Biologia Cellulare e Neuroscienze, Istituto Superiore di Sanità, Rome, Italy

    Serena Cecchetti & Daniela Merlo

  9. IRCCS-San Raffaele Pisana, Rome, Italy

    Alessio Cardinale & Daniela Merlo

  10. Istituto di Clinica Pediatrica, Università Cattolica del Sacro Cuore, Rome, Italy

    Giuseppe Zampino

  11. Dipartimento di Pediatria, Università degli Studi di Bologna, Bologna, Italy

    Laura Mazzanti

  12. Sezione di Genetica Medica, Ospedale Bambino Gesù, Rome, Italy

    Maria C Digilio

  13. Institute of Medical Genetics, University of Zurich, Schwerzenbach, Switzerland

    Deborah Bartholdi

  14. Institut für Humangenetik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany

    Kerstin Kutsche

  15. Dipartimento di Pediatria, Università di Torino, Turin, Italy

    Giovanni B Ferrero

  16. Dipartimento di Pediatria, Ostetricia e Medicina della Riproduzione, Università di Siena, Siena, Italy

    Cecilia Anichini

  17. Clinica Pediatrica I, IRCCS Fondazione Policlinico Milano, Milan, Italy

    Angelo Selicorni

  18. Unità Operativa di Genetica Medica, Policlinico S. Orsola-Malpighi, Bologna, Italy

    Cesare Rossi

  19. Dipartimento di Pediatria, Università di Padova, Padua, Italy

    Romano Tenconi

  20. Institute of Human Genetics, University Hospital Erlangen, University of Erlangen-Nuremberg, Erlangen, Germany

    Martin Zenker

  21. Center for Molecular Cardiology and Departments of Pediatrics and Genetics & Genomic Sciences, Mount Sinai School of Medicine, New York, New York, USA

    Bruce D Gelb

Authors
  1. Viviana Cordeddu
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Contributions

V.C. and V.F. were responsible for mutation analysis and biochemistry, E.D.S., S.M. and P.B. were responsible for the generation and phenotypic characterization of transgenic C. elegans strains, L.A.P., J.M., W.S. and A.L. performed high-throughput resequencing, A.S., F.L. and C.R. did mutation analysis, A.M. and R.I. did protein network analysis, S.C. did the confocal laser scanning microscopy, A.C., E.F. and D.M. were responsible for functional studies, G.Z., L.M., M.C.D., D.B., K.K., C.A., A.S., G.B.F., R.T., M.Z. and B.D. obtained DNA specimens from patients and did clinical evaluation, and B.D.G. and M.T. were responsible for the project planning, data analysis and preparation of manuscript.

Corresponding authors

Correspondence to Bruce D Gelb or Marco Tartaglia.

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Cordeddu, V., Di Schiavi, E., Pennacchio, L. et al. Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair. Nat Genet 41, 1022–1026 (2009). https://doi.org/10.1038/ng.425

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