Medical Hypotheses
Volume 73, Issue 1 , Pages 56-59, July 2009

GNAI2 and regulators of G protein signaling as a potential Noonan syndrome mechanism

  • Xinyan Huang

      Affiliations

    • Department of Pharmacology, University of Michigan, 1301 MSRB III, Ann Arbor, MI 48109, United States
  • ,
  • Ying Fu

      Affiliations

    • Department of Pharmacology, University of Michigan, 1301 MSRB III, Ann Arbor, MI 48109, United States
  • ,
  • Raelene A. Charbeneau

      Affiliations

    • Department of Pharmacology, University of Michigan, 1301 MSRB III, Ann Arbor, MI 48109, United States
  • ,
  • Richard R. Neubig

      Affiliations

    • Department of Pharmacology, University of Michigan, 1301 MSRB III, Ann Arbor, MI 48109, United States
    • Department of Internal Medicine (Cardiovascular Medicine), University of Michigan, 1301 MSRB III, Ann Arbor, MI 48109, United States
    • Corresponding Author InformationCorresponding author. Address: Department of Pharmacology, University of Michigan, 1301 MSRB III, Ann Arbor, MI 48109, United States. Tel.: +1 734 763 3650; fax: +1 734 763 4450.

Received 14 January 2009; accepted 18 January 2009. published online 12 March 2009.

Summary 

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 Gαi2 (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 Gαi2 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 Gαi2 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.

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PII: S0306-9877(09)00092-9

doi:10.1016/j.mehy.2009.01.040

Medical Hypotheses
Volume 73, Issue 1 , Pages 56-59, July 2009