GNAI2 and regulators of G protein signaling as a potential Noonan syndrome mechanism.
Noonan syndrome (NS OMIM 163950) is a relatively common autosomal dominant developmental disorder characterized by short stature, specific facial features, and congenital cardiac anomalies. Approximately 50-66% of cases have defined mutations in the K-ras/Raf/MEK/ERK pathway that lead to constitutive signaling, but a significant number remain unexplained. We hypothesize that enhanced signaling through Galpha(i2) (from the GNAI2 gene) may also produce a NS-like phenotype. This is based on a recently described mouse model in which RGS-mediated inhibition of Galpha(i2) is prevented by a knock-in mutation (G184S) that blocks RGS binding [Huang et al., Mol. Cell. Biol. 2006;26:6870-9]. The mice have short body length, cardiac hypertrophy, a triangular face with wide-set eyes and ears, and hematologic alterations. There is a slight increase in ERK activation and a pronounced enhancement of PI3K/Akt phosphorylation in MEFs from these mice suggesting that abnormal increases in Galpha(i2) signaling could represent a novel upstream mechanism for NS. This suggests a novel set of candidate genes for NS (GNAI2 and RGS proteins) and if validated could have important implications for therapy as well.
Huang
Xinyan
X
Department of Pharmacology, University of Michigan, 1301 MSRB III, Ann Arbor, MI 48109, USA.
Fu
Ying
Y
Charbeneau
Raelene A
RA
Neubig
Richard R
RR
D000818:Animals; D051960:GTP-Binding Protein alpha Subunit, Gi2 / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008954:Models, Biological; D009634:Noonan Syndrome / Q000378:metabolism*; D015398:Signal Transduction
D019204:GTP-Binding Proteins; C498015:GNAI2 protein, human; D051960:GTP-Binding Protein alpha Subunit, Gi2