Quick Search:

is currently disabled due to reindexing of the ZORA database. Please use Advanced Search.
uzh logo
Browse by:
bullet
bullet
bullet
bullet

Zurich Open Repository and Archive 

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.

[img] PDF - Registered users only
1MB

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.

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 06:06
Last Modified:27 Nov 2013 19:28
Publisher:Nature Publishing Group
ISSN:1061-4036
Publisher DOI:10.1038/ng.425
Other Identification Number:10.1038/ng.425
Citations:Web of Science®. Times Cited: 93
Google Scholar™
Scopus®. Citation Count: 110

Users (please log in): suggest update or correction for this item

Repository Staff Only: item control page