Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair.
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.
Cordeddu
Viviana
V
Dipartimento di Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, Rome, Italy.
Di Schiavi
Elia
E
Pennacchio
Len A
LA
Ma'ayan
Avi
A
Sarkozy
Anna
A
Fodale
Valentina
V
Cecchetti
Serena
S
Cardinale
Alessio
A
Martin
Joel
J
Schackwitz
Wendy
W
Lipzen
Anna
A
Zampino
Giuseppe
G
Mazzanti
Laura
L
Digilio
Maria C
MC
Martinelli
Simone
S
Flex
Elisabetta
E
Lepri
Francesca
F
Bartholdi
Deborah
D
Kutsche
Kerstin
K
Ferrero
Giovanni B
GB
Anichini
Cecilia
C
Selicorni
Angelo
A
Rossi
Cesare
C
Tenconi
Romano
R
Zenker
Martin
M
Merlo
Daniela
D
Dallapiccola
Bruno
B
Iyengar
Ravi
R
Bazzicalupo
Paolo
P
Gelb
Bruce D
BD
Tartaglia
Marco
M
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*
D000199:Actins; D005456:Fluorescent Dyes; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins; C112913:SHOC2 protein, human; D019814:Myristic Acid; C007293:DAPI
Science. 2005 Aug 12;309(5737):1078-83
16099987
Cell. 1998 Jul 10;94(1):119-30
9674433
Nucleic Acids Res. 2003 Jan 1;31(1):248-50
12519993
Nat Chem Biol. 2006 Nov;2(11):584-90
17051234
BMC Bioinformatics. 2007 Oct 04;8:372
17916244
Am J Med Genet. 1994 Nov 1;53(2):187-91
7856646
Nat Rev Cancer. 2007 Apr;7(4):295-308
17384584
J Med Genet. 2006 Nov;43(11):833-42
16825433
Dev Biol. 2002 Jan 15;241(2):339-48
11784116
Am J Med Genet A. 2003 Apr 30;118A(3):279-86
12673660
Nat Genet. 2003 Jun;34(2):148-50
12717436
Nat Genet. 2007 Jan;39(1):75-9
17143282
Blood. 2004 Mar 15;103(6):2325-31
14644997
Nucleic Acids Res. 2007 Jan;35(Database issue):D572-4
17135203
J Biol Chem. 2001 Mar 30;276(13):10505-13
11124252
Am J Med. 1976 Mar;60(3):447-56
1258892
Bioinformatics. 2005 Mar;21(6):827-8
15513994
J Biol Chem. 2001 Oct 26;276(43):39501-4
11527981
Proc Natl Acad Sci U S A. 1998 Jun 9;95(12):6903-8
9618511
Genes Dev. 2000 Apr 15;14(8):895-900
10783161
Genetics. 2000 Nov;156(3):1097-116
11063687
Nucleic Acids Res. 2007 Jan;35(Database issue):D561-5
17145710
Nucleic Acids Res. 2001 Jan 1;29(1):239-41
11125102
EMBO J. 1991 Dec;10(12):3959-70
1935914
Mol Cell. 2006 Apr 21;22(2):217-30
16630891
WormBook. 2005 Jun 25;:1-28
18050418
Cell Signal. 1997 Jan;9(1):15-35
9067626
J Med Genet. 1987 Jan;24(1):9-13
3543368
Mol Pharmacol. 1987 Feb;31(2):159-68
3027528
Nat Med. 2004 Aug;10(8):849-57
15273746
Dermatologica. 1991;182(4):247-9
1884862