MEK-ERK pathway modulation ameliorates disease phenotypes in a mouse model of Noonan syndrome associated with the Raf1L613V mutation

Abstract

Hypertrophic cardiomyopathy (HCM) is a leading cause of sudden death in children and young adults. Abnormalities in several signaling pathways are implicated in the pathogenesis of HCM, but the role of the RAS-RAF-MEK-ERK MAPK pathway has been controversial. Noonan syndrome (NS) is one of several autosomal-dominant conditions known as RASopathies, which are caused by mutations in different components of this pathway. Germline mutations in RAF1 (which encodes the serine-threonine kinase RAF1) account for approximately 3%-5% of cases of NS. Unlike other NS alleles, RAF1 mutations that confer increased kinase activity are highly associated with HCM. To explore the pathogenesis of such mutations, we generated knockin mice expressing the NS-associated Raf1 L613V mutation. Like NS patients, mice heterozygous for this mutation (referred to herein as L613V/+ mice) had short stature, craniofacial dysmorphia, and hematologic abnormalities. Valvuloseptal development was normal, but L613V/+ mice exhibited eccentric cardiac hypertrophy and aberrant cardiac fetal gene expression, and decompensated following pressure overload. Agonist-evoked MEK-ERK activation was enhanced in multiple cell types, and postnatal MEK inhibition normalized the growth, facial, and cardiac defects in L613V/+ mice. These data show that different NS genes have intrinsically distinct pathological effects, demonstrate that enhanced MEK-ERK activity is critical for causing HCM and other RAF1-mutant NS phenotypes, and suggest a mutation-specific approach to the treatment of RASopathies.

Growth hormone and noonan syndrome: update in dysfunctional signaling aspects and in therapy for short stature

“…In agreement with this, earlier reports incidentally showed that Mek inhibitors can rescue growth defect in other NS mouse models (RAF1 L613V/+ and SOS1 E846K/E846K ) [7,66]. Altogether, these reports suggest that pharmacological regulation of Ras/MAPK could be an alternative approach to treat short stature in NS patients, even though a lot requires to be accomplished to assess the efficacy and safety of these Figure 1.…”

Next-generation sequencing identifies rare variants associated with Noonan syndrome

“…For example, mice that carry a Sos1 mutation develop multiple NS features, and these defects can be prevented or their expression reduced by MEK inhibitor treatment during the early stages of life (47). Postnatal MEK inhibitor treatment also reverses some NS symptoms in Raf1 mutant mice (48), and rapamycin normalizes HCM in LS mouse models (5). Analogous models for the new NS genes defined here and by others (28) could prove important for personalizing RASopathy therapy.…”

Signaling to Cardiac Hypertrophy: Insights from Human and Mouse RASopathies

“…The identification of a Thr188-phosphorylation site on ERK2 might be a first step in this direction: this phosphorylation can selectively activate hypertrophic ERK1/2 functions and, therefore, may be targeted without dangerous side effects. Mutant mice that lack this phosphorylation site show preserved cardiac structure and function and attenuated hypertrophic response, indeed demonstrating that ERK1/2 can be selectively targeted, at least in the adult patient (59).…”

“…RAF1 mutations have been more frequently found to be associated with HCM, and nearly all NS patients with RAF1 mutations exhibit HCM (58). Like NS patients, mice heterozygous for the NS-associated RAF1 mutation exhibit eccentric cardiac hypertrophy (59). A mouse model of a constitutively active form of BRAF has also been created (60).…”

“…Evidence from cultured cardiac myocytes exposed to a MEK1-specific inhibitor demonstrated the critical contribution of the ERK pathway to hypertrophy (62,63). In vivo, inhibition of MEK attenuated cardiac growth in both induced and genetic models of hypertrophy (48,59,64,65). Final activation of MAPK has also been documented in different heart diseases (66,67).…”