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


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.

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 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.

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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Medical Genetics
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Date:16 August 2009
Deposited On:19 Feb 2010 06:06
Last Modified:05 Apr 2016 13:58
Publisher:Nature Publishing Group
ISSN:1061-4036
Publisher DOI:10.1038/ng.425
Other Identification Number:10.1038/ng.425
Permanent URL: http://doi.org/10.5167/uzh-31583

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