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

• Published in: Nature genetics Vol. 41; no. 9; pp. 1022 - 1026
• Main Authors: Cordeddu, Viviana, Di Schiavi, Elia, Pennacchio, Len A, Ma'ayan, Avi, Sarkozy, Anna, Fodale, Valentina, Cecchetti, Serena, Cardinale, Alessio, Martin, Joel, Schackwitz, Wendy, Lipzen, Anna, Zampino, Giuseppe, Mazzanti, Laura, Digilio, Maria C, Martinelli, Simone, Flex, Elisabetta, Lepri, Francesca, Bartholdi, Deborah, Kutsche, Kerstin, Ferrero, Giovanni B, Anichini, Cecilia, Selicorni, Angelo, Rossi, Cesare, Tenconi, Romano, Zenker, Martin, Merlo, Daniela, Dallapiccola, Bruno, Iyengar, Ravi, Bazzicalupo, Paolo, Gelb, Bruce D, Tartaglia, Marco
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.09.2009; Nature Publishing Group
• Subjects: Actins - metabolism; Agriculture; Amino acids; Animal Genetics and Genomics; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Caenorhabditis elegans; Cancer Research; Cell Nucleus - metabolism; Cytoskeleton - metabolism; Diseases of the osteoarticular system; DNA binding proteins; Fluorescent Antibody Technique, Indirect; Fluorescent Dyes - metabolism; Fundamental and applied biological sciences. Psychology; Gene Function; Gene mutations; Genetic aspects; Genetic testing; Genetics of eukaryotes. Biological and molecular evolution; Genotype & phenotype; Germ-Line Mutation; Graph theory; Growth hormones; Hair; Hair - growth & development; Health aspects; Human Genetics; Humans; Indoles - metabolism; Intracellular Signaling Peptides and Proteins - genetics; letter; Malformations and congenital and or hereditary diseases involving bones. Joint deformations; Medical sciences; Mutation; Mutation, Missense; Myristic Acid - metabolism; Noonan syndrome; Noonan Syndrome - genetics; Noonan Syndrome - metabolism; Physiological aspects; Proteins; Risk factors; Signal transduction; Statistical analysis; Statistical methods; Translocation; United States; Italy; Germany; Skin disease; Nervous system diseases; Loose anagen hair syndrome; Noonan syndrome; Diseases of the osteoarticular system; Cardiovascular disease; Mutation; Osteochondrodysplasia; Protein; Genetic disease
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/ng.425

Marco Tartaglia and colleagues report the identification of mutations of SHOC2 in individuals with Noonan-like syndrome with loose anagen hair. The mutations cause aberrantly acquired N-myristoylation of SHOC2 resulting in aberrant targeting of SHOC2 to the plasma membrane. SHOC2 is believed to function as a scaffold linking RAS to downstream signal transducers. 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 1 , 2 . We show that aberrantly acquired N-myristoylation of SHOC2, a leucine-rich repeat–containing protein that positively modulates RAS-MAPK signal flow 3 , 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 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.