Abstract：
: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.
journal_name
Med Hypothesesjournal_title
Medical hypothesesauthors
Huang X,Fu Y,Charbeneau RA,Neubig RRdoi
10.1016/j.mehy.2009.01.040subject
Has Abstractpub_date
2009-07-01 00:00:00pages
56-9issue
1eissn
0306-9877issn
1532-2777pii
S0306-9877(09)00092-9journal_volume
73pub_type
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