2. Academic Validation
  3. Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair

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

  • Nat Genet. 2009 Sep;41(9):1022-6. doi: 10.1038/ng.425.
Viviana Cordeddu 1,  Elia Di Schiavi,  Len A Pennacchio,  Avi Ma'ayan,  Anna Sarkozy,  Valentina Fodale,  Serena Cecchetti,  Alessio Cardinale,  Joel Martin,  Wendy Schackwitz,  Anna Lipzen,  Giuseppe Zampino,  Laura Mazzanti,  Maria C Digilio,  Simone Martinelli,  Elisabetta Flex,  Francesca Lepri,  Deborah Bartholdi,  Kerstin Kutsche,  Giovanni B Ferrero,  Cecilia Anichini,  Angelo Selicorni,  Cesare Rossi,  Romano Tenconi,  Martin Zenker,  Daniela Merlo,  Bruno Dallapiccola,  Ravi Iyengar,  Paolo Bazzicalupo,  Bruce D Gelb,  Marco Tartaglia
Affiliations

Affiliation

  • 1 Dipartimento di Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, Rome, Italy.
PMID: 19684605 DOI: 10.1038/ng.425
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 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 SHOC2(S2G) in vitro enhanced MAPK activation in a cell type-specific fashion. Induction of SHOC2(S2G) 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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