A Novel HRAS Mutation Independently Contributes to Left Ventricular Hypertrophy in a Family with a Known MYH7 Mutation

Abstract

Several genetic conditions can lead to left ventricular hypertrophy (LVH). Among them, hypertrophic cardiomyopathy (HCM), caused by mutations in sarcomere genes, is the most common inherited cardiac disease. Instead, RASopathies, a rare class of disorders characterized by neuro-cardio-facial-cutaneous abnormalities and sometimes presenting with LVH, are caused by mutations in the RAS-MAPK pathway. We report on a 62-years-old male who presented isolated severe obstructive LVH but did not carry the sarcomere mutation previously identified in his affected relatives. By exome sequencing, we detected a novel mutation in HRAS gene (NM_005343.2:p.Arg68Trp), present also in the proband’s daughter, who showed mild LVH and severe intellectual disability. The cardiac phenotype was indistinguishable between family members carrying either mutation. In silico studies suggested that the mutated HRAS protein is constitutionally activated. Consistently, functional characterization in vitro confirmed elevated HRAS-GTP accumulation and downstream RAS-MAPK pathway activation that are known to drive cell proliferation in LVH. Our study emphasizes the role of RAS signaling in cardiac hypertrophy and highlights the complexity in differential diagnosis of RASopathies. In fact, the mild features of RASopathy and the recurrence of sarcomeric HCM in this family delayed the correct diagnosis until comprehensive genetic testing was performed.

miRNA Genetic Variants Alter Their Secondary Structure and Expression in Patients With RASopathies Syndromes

“…The WES approach enables studies of the patients within an environmental and clinical context through large-scale cohort trials and data processing with a focus on the associations among molecular biology, disease and health phenotypes to assure a more accurate diagnosis, leading to the establishment of individualized disease prevention and treatment programmes (Tetreault et al, 2015; Collins et al, 2016; Tebani et al, 2016). Moreover, WES has allowed the identification of new genes associated to the clinical description of patients with RASopathies (Niguidula et al, 2018; Matias et al, 2019), such as RIT1 (Aoki et al, 2013), A2ML1 (Vissers et al, 2015), RASA2, SPRY1 (Chen et al, 2014), SOS2, LZTR1 (Yamamoto et al, 2015; Umeki et al, 2019), PPP1CB (Gripp et al, 2016), CBL (Coe et al, 2017), and MRAS (Higgins et al, 2017), as well as new mutations in genes of the RAS/MAPK pathway (Carapito et al, 2014; Sana et al, 2016; Coe et al, 2017; Harms et al, 2018; Valera et al, 2018).…”

Cardiac‐specific deletion of FDPS induces cardiac remodeling and dysfunction by enhancing the activity of small GTP‐binding proteins

“…The role of FDPS in cardiac homeostasis 447 model [17], and a dominant-negative Ras mutation protects against ventricular remodeling in response to pressure overload [25]. Additionally, a mutation that resulted in constitutive activation demonstrated that H-Ras can exacerbate pathological cardiac hypertrophy [26]. Moreover, the use of simvastatin or carabin to interfere with Ras signaling ameliorated cardiac hypertrophy [27].…”

Left Ventricular Hypertrophy in Pediatric Hypertension: A Mini Review

“…Similarly, diabetic children have significant changes in LV dimensions, and girls are more affected than boys ( 55 ). Finally, there is strong evidence for the genetic influence on LVH prevalence across several study designs, datasets and ethnicities ( 56 – 60 ), and several genetic conditions, i.e., hypertrophic cardiomyopathy, caused by mutations in sarcomere genes ( 61 ), and RASopathies are causally associated with LVH ( 62 ). However, specific genetic influences on prevalence of HTN-associated LVH are currently unknown.…”