MEK-ERK pathway modulation ameliorates disease phenotypes in a mouse model of Noonan syndrome associated with the RAF1 (L613V) mutation

Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
The Journal of clinical investigation (Impact Factor: 13.22). 02/2011; 121(3):1009-25. DOI: 10.1172/JCI44929
Source: PubMed


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.

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    • "E-mail: Article first published online in Wiley Online Library ( 00 Month 2014 DOI 10.1002/ajmg.a.36588 Ó 2014 Wiley Periodicals, Inc. Noonan syndrome [Wu et al., 2011] "
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    • "Clinically, activating mutations in Ras and its target Raf result in Costello and Noonen syndromes respectively, both of which induce cardiomyopathy amongst other abnormalities (Lin et al., 2011; Wu et al., 2011). Induction of hypertrophy by activated Ras and Raf is ERK1/2 dependent, suggesting that this kinase is responsible for the hypertrophic response to Ras and Raf activation (Harris et al., 2004; Wu et al., 2011). However, although it has been intensively investigated, the precise role and function of activated ERK1/2 in the heart remains controversial (Bueno and Molkentin, 2002; Kehat and Molkentin, 2010). "
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    • "Assessment of ERK/MAPK signaling in vitro and in vivo in hearts from these mice revealed increased activation of Mek1/2 and ERK1/2, suggesting that blockade of the ERK/MAPK signaling pathway in these mice could be beneficial. Indeed, treatment with the MEK inhibitor, PD0325901, blocked and reversed HCM in vivo (Wu et al. 2011). "
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