SOS1 Gain of Function Variants in Dilated Cardiomyopathy

Background - Dilated cardiomyopathy (DCM) is a genetically heterogeneous cardiac disease characterized by progressive ventricular enlargement and reduced systolic function. Here, we report genetic and functional analyses implicating the RAS signaling protein, SOS1, in DCM pathogenesis. Methods - Exome sequencing was performed on 412 probands and family members from our DCM cohort, identifying several SOS1 variants with potential disease involvement. As several lines of evidence have implicated dysregulated RAS signaling in the pathogenesis of DCM, we assessed functional impact of each variant on activation of ERK, AKT, and JNK pathways. Relative expression levels were determined by western blot in HEK293T cells transfected with variant or wild-type human SOS1 expression constructs. Results - A rare SOS1 variant [c.571G>A, p.(Glu191Lys)] was found to segregate alongside an A-band Titin (TTN) truncating variant in a pedigree with aggressive, early onset DCM. Reduced disease severity in the absence of the SOS1 variant suggested its potential involvement as a genetic risk factor for DCM in this family. Exome sequencing identified five additional SOS1 variants with potential disease involvement in four other families [c.1820T>C, p.(Ile607Thr); c.2156G>C, p.(Gly719Ala); c.2230A>G, p.(Arg744Gly); c.2728G>C, p.(Asp910His); c.3601C>T, p.(Arg1201Trp)]. Impacted amino acids occupied a number of functional domains relevant to SOS1 activity, including the N-terminal histone fold (HF), as well as the C-terminal RAS-exchange motif (REM), CDC25, and proline-rich (PR) tail domains. Increased pERK expression relative to wild-type levels was seen for all six SOS1 variants, paralleling known disease-relevant SOS1 signaling profiles. Conclusions - These data support gain of function variation in SOS1 as a contributing factor to isolated DCM.

Keywords: SOS1 protein; son of sevenless protein.