RapGEF4

Mutations in the RAPGEF4 gene are implicated in the pathogenesis of several neuropsychiatric conditions including autism spectrum disorders (ASD) and major depressive disorder. Variants in RAPGEF4 gene have also been found in patients with the Carney Complex disorder that is characterized by multiple benign tumors. In addition, RAPGEF4 is involved in glucose metabolism and insulin secretion, making it a potential therapeutic target for type 2 diabetes. Below we summarize current knowledge and useful information about this gene.

Biological Function

RAPGEF4 encodes for the Rap Guanine Nucleotide Exchange Factor 4, also called Epac2 or cAMP-GEF.
RAPGEF4 gene is comprised of 31 exons and 30 introns situated on chromosome 2q31.
RAPGEF4 is involved in cyclic AMP (cAMP) mediated transduction by activating the small GTPases Rap1 and Rap2 that play roles in cell signaling and various cellular processes.
Three isoforms of Epac2 have been identified: Epac2A, Epac2B and Epac2C. Epac2A is mainly expressed in the brain and neuroendocrine and endocrine tissues. Epac2B is mainly expressed in the adrenal gland, while Epac2C is predominantly found in the liver.
In the brain, Epac2 is abundantly expressed in neuronal cells and is involved in multiple processes including neurotransmitter release, neuronal differentiation and neurite growth.
Epac2 plays an important role in synaptic plasticity, thus controlling higher functions such as memory and learning.

Mutations

The RAPGEF4 gene has been implicated in multiple neuropsychiatric conditions including ASD and major depression disorder, as well as other disorders such as the Carney Complex disease.
RAPGEF4 is a known FMRP target and has been suggested as a potential autism candidate gene.
Four rare nonsynonymous variants have been identified in 5 families, where they segregated with the autism phenotype.
RAPGEF4 gene is considered a novel ASD-risk gene associated with a negative regulation of synaptic transmission.

Incidence

RAPGEF4 is considered a novel ASD-risk gene, with limited knowledge about its incidence. Very few studies have yet evaluated the prevalence of RAPGEF4 mutations in patients with ASD.

Associated Conditions

There are no clinical conditions currently associated with RAPGEF4 mutations.

Research at Northwestern

Research from the Contractor Lab and Penzes Lab has been focused on understanding the signaling pathway and function of RAPGEF4/Epac2 and its implications for disease.

Key publications include:

Epac2 mediates cAMP-dependent potentiation of neurotransmission in the hippocampus
Fernandes HB, Riordan S, Nomura T, Remmers CL, Kraniotis S, Marshall JJ, Kukreja L, Vassar R, Contractor A.
J Neurosci. 2015 Apr 22;35(16):6544-53.
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Epac2-mediated dendritic spine remodeling: implications for disease
Penzes P, Woolfrey KM, Srivastava DP.
Mol Cell Neurosci. 2011 Feb;46(2):368-80.
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Loss of EPAC2 alters dendritic spine morphology and inhibitory synapse density
Jones KA, Sumiya M, Woolfrey KM, Srivastava DP, Penzes P.
Mol Cell Neurosci. 2019 Jul;98:19-31.
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Important publications from other laboratories

Structure and functional roles of Epac2 (Rapgef4)
Sugawara K, Shibasaki T, Takahashi H, Seino S.
Gene. 2016 Jan 10;575(2 Pt 3):577–83.
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Screening of nine candidate genes for autism on chromosome 2q reveals rare nonsynonymous variants in the cAMP-GEFII gene
Bacchelli E, Blasi F, Biondolillo M, et al.
Mol Psychiatry. 2003;8:916–924.
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Inherited and de novo genetic risk for autism impacts shared networks
Ruzzo EK, Pérez-Cano L, Jung JY, Wang LK, Kashef-Haghighi D, et al.
Cell. 2019 Aug 8;178(4):850–866.e26.
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