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 residue. We show that aberrantly acquired N-myristoylation of SHOC2, a leucine-rich repeat–containing protein that positively modulates RAS-MAPK signal flow, 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) 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.

DOI: 10.1038/ng.425

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@article{Cordeddu2009MutationOS, title={Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair}, author={Viviana Cordeddu and Elia Di Schiavi and Len A. Pennacchio and Avi Ma'ayan and Anna Sarkozy and Valentina Fodale and Serena Cecchetti and Alessio Cardinale and Joel A Martin and Wendy S. Schackwitz and Anna Lipzen and Giuseppe Zampino and Laura Mazzanti and Maria Christina Digilio and Simone Elias Martinelli and Elisabetta Flex and Francesca Romana Lepri and Deborah Bartholdi and Kerstin Kutsche and Giovanni Battista Ferrero and Cecilia Anichini and Angelo Selicorni and Cesare Rossi and Romano Tenconi and Martin Zenker and Daniela Merlo and Bruno Dallapiccola and Ravi Iyengar and Paolo Bazzicalupo and Bruce D Gelb and Marco Tartaglia}, journal={Nature Genetics}, year={2009}, volume={41}, pages={1022-1026} }