Developmental SHP2 dysfunction underlies cardiac hypertrophy in Noonan syndrome with multiple lentigines

Lauriol, Jessica; Cabrera, Janel R.; Roy, Amrita; Keith, Kimberly; Hough, Sara M.; Damilano, Federico; Wang, Bonnie; Segarra, Gabriel C.; Flessa, Meaghan E.; Miller, Lauren E.; Das, Saumya; Bronson, Roderick T.; Lee, Kyu‐Ho; Kontaridis, Maria I.

doi:10.1172/jci80396

Cited by 30 publications

(36 citation statements)

References 68 publications

(80 reference statements)

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“…Previous pharmacological studies have shown that treatment of cardiomyocytes with an AKT inhibitor could prevent the hypertrophic response evoked by stimulation with various agonists [18–21]. Inhibition of AKT/mTOR signaling also attenuates or reverses pressure overload-associated cardiac hypertrophy [19,22,23], supporting our findings that there is a potential regulatory role for AKT/mTOR in pathological HCM in NSML [11,12]. …”

Section: Discussionsupporting

confidence: 86%

In vivo efficacy of the AKT inhibitor ARQ 092 in Noonan Syndrome with multiple lentigines-associated hypertrophic cardiomyopathy

et al. 2017

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Noonan Syndrome with Multiple Lentigines (NSML, formerly LEOPARD syndrome) is an autosomal dominant "RASopathy" disorder manifesting in congenital heart disease. Most cases of NSML are caused by catalytically inactivating mutations in the protein tyrosine phosphatase (PTP), non-receptor type 11 (PTPN11), encoding the SH2 domain-containing PTP-2 (SHP2) protein. We previously generated knock-in mice harboring the PTPN11 mutation Y279C, one of the most common NSML alleles; these now-termed SHP2Y279C/+ mice recapitulate the human disorder and develop hypertrophic cardiomyopathy (HCM) by 12 weeks of age. Functionally, heart and/or cardiomyocyte lysates from SHP2Y279C/+ mice exhibit increased basal and agonist-induced AKT and mTOR activities. Here, we sought to determine whether we could reverse the hypertrophy in SHP2Y279C/+ mice using ARQ 092, an oral and selective allosteric AKT inhibitor currently in clinical trials for patients with PI3K/AKT-driven tumors or Proteus syndrome. We obtained echocardiographs of SHP2Y279C/+ and wildtype (SHP2+/+) littermates, either in the presence or absence of ARQ 092 at 12, 14, and 16 weeks of age. While SHP2Y279C/+ mice developed significant left ventricular hypertrophy by 12 weeks, as indicated by decreased chamber dimension and increased posterior wall thickness, treatment of SHP2Y279C/+ mice with ARQ 092 normalized the hypertrophy in as early as 2 weeks following treatment, with hearts comparable in size to those in wildtype (SHP2+/+) mice. In addition, we observed an increase in fractional shortening (FS%) in SHP2Y279C/+ mice, an effect of increased compensatory hypertrophy, which was not apparent in SHP2Y279C/+ mice treated with ARQ 092, suggesting functional improvement of HCM upon treatment with the AKT inhibitor. Finally, we found that ARQ 092 specifically inhibited AKT activity, as well as its downstream effectors, PRAS and S6RP in NSML mice. Taken together, these data suggest ARQ 092 may be a promising novel therapy for treatment of hypertrophy in NSML patients.

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Section: Discussionsupporting

confidence: 86%

In vivo efficacy of the AKT inhibitor ARQ 092 in Noonan Syndrome with multiple lentigines-associated hypertrophic cardiomyopathy

et al. 2017

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“…Regardless, our results, along with other recent work 44,60,64 , argue for a paradigm shift away from the myocyte-centric view of cardiac development and disease. Aberrant EC signaling is likely a recurring pathogenic mechanism in RASopathy-associated cardiomyopathy, and might well contribute to other genetic or even secondary forms of LVH.…”

Section: Discussionsupporting

confidence: 65%

“…While our manuscript was in revision, Lauriol et al . reported that NS-ML-associated hypertrophy arises from expression of catalytically impaired SHP2 ( PTPN11 ) solely in EC 64 . They observed ventricular thinning and delayed septal closure in developing hearts, which they attributed to increased AKT and decreased FOXP1 and NOTCH1 signaling.…”

Section: Discussionmentioning

confidence: 99%

Cellular Interplay and Cytokine Hierarchy Cause Pathological Cardiac Hypertrophy inRAF1-Mutant Noonan Syndrome

Yin

Platt

Tian

et al. 2017

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“…A genetic mutation of the RAS‐MAPK signalling pathway has been highlighted as a cause of cardiac hypertrophy associated with Noonan syndrome . Previous reports indicated how mutations in the PTPN11 gene induces cardiac hypertrophy and cardiovascular diseases . However, the intracellular role of KRAS mutation in Noonan syndrome is largely unknown …”

Section: Discussionmentioning

confidence: 99%

Double‐chambered right ventricle complicated by hypertrophic obstructive cardiomyopathy diagnosed as Noonan syndrome

et al. 2020

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We present a case of double-chambered right ventricle (DCRV) complicated by hypertrophic obstructive cardiomyopathy (HOCM) in KRAS mutation-associated Noonan syndrome. The diagnosis was incidental and made during diagnostic testing for an intradural extramedullary tumour. Spinal compression, if not surgically treated, may cause paralysis of the extremities. We decided to pursue pharmacological therapy to control biventricular obstructions and reduce the perioperative complication rate. We initiated treatment with cibenzoline and bisoprolol; the doses were titrated according to the response. After 2 weeks, the peak pressure gradient of the two RV chambers decreased from 101 to 68 mmHg, and the LV peak pressure gradient decreased from 109 to 14 mmHg. Class 1A antiarrhythmic drugs and β-blockers decreased the severe pressure gradients of biventricular obstructions caused by DCRV and HOCM. The patient was able to undergo surgery to remove the intradural extramedullary tumour, which was diagnosed as schwannoma.

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Developmental SHP2 dysfunction underlies cardiac hypertrophy in Noonan syndrome with multiple lentigines

Cited by 30 publications

References 68 publications

In vivo efficacy of the AKT inhibitor ARQ 092 in Noonan Syndrome with multiple lentigines-associated hypertrophic cardiomyopathy

In vivo efficacy of the AKT inhibitor ARQ 092 in Noonan Syndrome with multiple lentigines-associated hypertrophic cardiomyopathy

Cellular Interplay and Cytokine Hierarchy Cause Pathological Cardiac Hypertrophy inRAF1-Mutant Noonan Syndrome

Double‐chambered right ventricle complicated by hypertrophic obstructive cardiomyopathy diagnosed as Noonan syndrome

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