Cardiomyopathies in Noonan syndrome and the other RASopathies

Abstract

Noonan syndrome and related disorders (Noonan syndrome with multiple lentigines, Costello syndrome, cardiofaciocutaneous syndrome, Noonan syndrome with loose anagen hair, and other related traits) are autosomal dominant traits. Mutations causing these disorders alter proteins relevant for signaling through RAS. Thus, these traits are now collectively called the RASopathies. While the RASopathies have pleiomorphic features, this review will focus on the hypertrophic cardiomyopathy observed in varying percentages of all of these traits. In addition, inherited abnormalities in one pathway gene, RAF1, cause pediatric-onset dilated cardiomyopathy. The pathogeneses for the RASopathy-associated cardiomyopathies are being elucidated, principally using animal models, leading to genotype-specific insights into how signal transduction is perturbed. Based on those findings, small molecule therapies seem possible for RASopathy-associated cardiomyopathies.

Figure 1. Survival by age and congestive heart failure in children with Noonan syndrome and hypertrophic cardiomyopathy

Estimated survival since diagnosis of hypertrophic cardiomyopathy (CM) in 74 children with Noonan syndrome by age and congestive heart failure (CHF) status at the time of HCM diagnosis. Log-rank P < .001. The size of the risk set is shown below the x-axis. The subgroup of 3 cases with congestive heart failure who were diagnosed at age ≥6 months is not shown (one known to survive 5.5 months post diagnosis, and 2 were not seen after diagnosis). Reprinted with permission from the American Heart Journal [5].

Figure 2. Rapamycin normalizes hypertrophic cardiomyopathy in Noonan syndrome with multiple lentigines mice

(A) Hematoxylin & eosin-stained longitudinal sections of hearts from wild-type (WT) and Noonan syndrome with multiple lentigines (LS/+) mice. Note normalization of hypertrophy in LS/+ hearts after rapamycin treatment (original magnification, ×100). (B) Reticulin stain of paraffin-embedded heart sections from 16-week-old WT and LS/+ mice (original magnification, ×400). (C) Quantification of average area (in μm²) of cardiomyocytes (200–500 cells counted/group) from WT or LS/+ cardiomyocytes isolated from mice that were either vehicle- or rapamycin-treated (2 mg/kg body weight) daily by i.p. injection for 4 weeks, then weekly for 4 weeks. Results are shown as the mean ± standard error of the mean. *P < 0.05, †P < 0.05. (D) Heart weight to body weight ratios of WT and LS/+ mice with vehicle- or rapamycin-treatment, as indicated. *P < 0.05, †P < 0.001. Reprinted with permission from the Journal for Clinical Investigation [35].

Figure 3. Dilated cardiomyopathy-associated RAF1 mutants induce heart defects mimicking heart failure phenotype in zebrafish

Lateral view of zebrafish embryos at 72 hours post fertilization (hpf) that were uninjected (a), injected with WT (b), p.Pro332Ala (c) or p. Leu603Pro (d) RAF1 mRNA. The two representative dilated cardiomyopathy mutants (p.Pro332Ala and p.Leu603Pro) showing string-like cardiac chambers (asterisk) with pericardial edema (arrow). Treatment with rapamycin rescued the heart failure phenotypes in the p.Pro332Ala and p.Leu603Pro RAF1 mRNA-injected embryos (e and f, respectively). Scale bar, 500 μm. g. Percentage of zebrafish embryos at 72 hpf after injection of the indicated RAF1 mRNA exhibiting heart defects with and without rapamycin treatment (n=150 in each group). h. Measurements of mutant heart rate showing severe bradycardia at 72 hpf. Data represent means ± SD of 30 embryos. Reprinted with permission from Nature Genetics [38].