title: Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair.
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.
authors.affiliation: Dipartimento di Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Viviana
authors.initials: V
authors.lastname: Cordeddu
authors.forename: Elia
authors.initials: E
authors.lastname: Di Schiavi
authors.forename: Len A
authors.initials: LA
authors.lastname: Pennacchio
authors.forename: Avi
authors.initials: A
authors.lastname: Ma'ayan
authors.forename: Anna
authors.initials: A
authors.lastname: Sarkozy
authors.forename: Valentina
authors.initials: V
authors.lastname: Fodale
authors.forename: Serena
authors.initials: S
authors.lastname: Cecchetti
authors.forename: Alessio
authors.initials: A
authors.lastname: Cardinale
authors.forename: Joel
authors.initials: J
authors.lastname: Martin
authors.forename: Wendy
authors.initials: W
authors.lastname: Schackwitz
authors.forename: Anna
authors.initials: A
authors.lastname: Lipzen
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Zampino
authors.forename: Laura
authors.initials: L
authors.lastname: Mazzanti
authors.forename: Maria C
authors.initials: MC
authors.lastname: Digilio
authors.forename: Simone
authors.initials: S
authors.lastname: Martinelli
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Flex
authors.forename: Francesca
authors.initials: F
authors.lastname: Lepri
authors.forename: Deborah
authors.initials: D
authors.lastname: Bartholdi
authors.forename: Kerstin
authors.initials: K
authors.lastname: Kutsche
authors.forename: Giovanni B
authors.initials: GB
authors.lastname: Ferrero
authors.forename: Cecilia
authors.initials: C
authors.lastname: Anichini
authors.forename: Angelo
authors.initials: A
authors.lastname: Selicorni
authors.forename: Cesare
authors.initials: C
authors.lastname: Rossi
authors.forename: Romano
authors.initials: R
authors.lastname: Tenconi
authors.forename: Martin
authors.initials: M
authors.lastname: Zenker
authors.forename: Daniela
authors.initials: D
authors.lastname: Merlo
authors.forename: Bruno
authors.initials: B
authors.lastname: Dallapiccola
authors.forename: Ravi
authors.initials: R
authors.lastname: Iyengar
authors.forename: Paolo
authors.initials: P
authors.lastname: Bazzicalupo
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Gelb
authors.forename: Marco
authors.initials: M
authors.lastname: Tartaglia
mesh_terms: D000199:Actins / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D019084:Fluorescent Antibody Technique, Indirect; D005456:Fluorescent Dyes / Q000378:metabolism; D018095:Germ-Line Mutation; D006197:Hair / Q000254:growth & development*; D006801:Humans; D007211:Indoles / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D009154:Mutation; D020125:Mutation, Missense; D019814:Myristic Acid / Q000378:metabolism*; D009634:Noonan Syndrome / Q000235:genetics / Q000378:metabolism*
chemical_list: D000199:Actins; D005456:Fluorescent Dyes; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins; C112913:SHOC2 protein, human; D019814:Myristic Acid; C007293:DAPI
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