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


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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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.

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Authors and Affiliations



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).

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