Human Molecular Genetics Advance Access originally published online on September 10, 2009
Human Molecular Genetics 2009 18(23):4629-4639; doi:10.1093/hmg/ddp430
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GIGYF2 gene disruption in mice results in neurodegeneration and altered insulin-like growth factor signaling
1 Division of Endocrinology and 2 Liver Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI 02903, USA, 3 Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA and 4 Parkinson Institute, Istituti Clinici di Perfezionamento, Milan 20126, Italy
* To whom correspondence should be addressed at: Division of Endocrinology, Rhode Island Hospital, One Hoppin Street, Suite 200, Providence, RI 02903, USA. Tel: +1 4014443420; Fax: +1 4014444921; Email: rsmith4{at}lifespan.org
Received June 19, 2009; Revised August 25, 2009; Accepted September 7, 2009
Grb10-Interacting GYF Protein 2 (GIGYF2) was initially identified through its interaction with Grb10, an adapter protein that binds activated IGF-I and insulin receptors. The GIGYF2 gene maps to human chromosome 2q37 within a region linked to familial Parkinson's disease (PARK11 locus), and association of GIGYF2 mutations with Parkinson's disease has been described in some but not other recent publications. This study investigated the consequences of Gigyf2 gene disruption in mice. Gigyf2 null mice undergo apparently normal embryonic development, but fail to feed and die within the first 2 post-natal days. Heterozygous Gigyf2+/– mice survive to adulthood with no evident metabolic or growth defects. At 12–15 months of age, the Gigyf2+/– mice begin to exhibit motor dysfunction manifested as decreased balance time on a rotating horizontal rod. This is associated with histopathological evidence of neurodegeneration and rare intracytoplasmic Lewy body-like inclusions in spinal anterior horn motor neurons. There are 
-synuclein positive neuritic plaques in the brainstem and cerebellum, but no abnormalities in the substantia nigra. Primary cultured embryo fibroblasts from Gigyf2 null mice exhibit decreased IGF-I-stimulated IGF-I receptor tyrosine phosphorylation and augmented ERK1/2 phosphorylation. These data provide further evidence for an important role of GIGYF2 in age-related neurodegeneration and IGF pathway signaling.
Present address: Universite Montpellier II, Montpellier, France.