Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-31583
Cordeddu, V; Di Schiavi, E; Pennacchio, L A; Ma'ayan, A; Sarkozy, A; Fodale, V; Cecchetti, S; Cardinale, A; Martin, J; Schackwitz, W; Lipzgen, A; Zampino, G; Mazzanti, L; Digilio, M C; Martinelli, S; Flex, E; Lepri, F; Bartholdi, D; Kutsche, K; Ferrero, G B; Anichini, C; Selicorni, A; Rossi, C; Tenconi, R; Zenker, M; Merlo, D; Dallapiccola, B; Iyengar, R; Bazzicalupo, P; Gelb, B D; Tartaglia, M (2009). Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair. Nature Genetics, 41(9):1022-1026.
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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 SHOC2S2Gin 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.
|Item Type:||Journal Article, refereed, original work|
|Communities & Collections:||04 Faculty of Medicine > Institute of Medical Genetics|
|DDC:||570 Life sciences; biology|
610 Medicine & health
|Date:||16 August 2009|
|Deposited On:||19 Feb 2010 07:06|
|Last Modified:||23 Nov 2012 16:35|
|Publisher:||Nature Publishing Group|
|Other Identification Number:||10.1038/ng.425|
|WoS Citation Count:||59|
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