PTPN11-associated mutations in the heart: has LEOPARD changed Its RASpots?

Abstract

In this review, we focus on elucidating the cardiac function of germline mutations in the PTPN11 gene, encoding the Src homology-2 (SH2) domain-containing protein tyrosine phosphatase SHP2. PTPN11 mutations cause LEOPARD syndrome (LS) and Noonan syndrome (NS), two disorders that are part of a newly classified family of autosomal dominant syndromes termed "RASopathies," which are caused by germline mutations in components of the RAS/RAF/MEK/ERK mitogen activating protein kinase pathway. LS and NS mutants have opposing biochemical properties, and yet, in patients, these mutations produce similar cardiac abnormalities. Precisely how LS and NS mutations lead to such similar disease etiology remains largely unknown. Recent complementary in vitro, ex vivo, and in vivo analyses reveal new insights into the functions of SHP2 in normal and pathological cardiac development. These findings also reveal the need for individualized therapeutic approaches in the treatment of patients with LS and NS and, more broadly, patients with the other "RASopathy" gene mutations as well.

Figure 1. Depiction of the signal transduction pathway and individual genes affected in each RASopathy disorder

The Rasopathy disorder associated with each gene is indicated in red. Positive regulatory interactions are indicated with black arrows, and negative regulatory interactions are indicated with black blunted arrows. CFCS, Cardiofaciocutaneous Syndrome; CS, Costello Syndrome; LS, LEOPARD Syndrome, NF1, Neurofibromatosis type 1; NFLS, Neurofibromatosis type 1–Like Syndrome; NFNS, Neurofibromatosis-NS; NS, Noonan Syndrome; NS/LAH, Noonan-like Syndrome with Loose Anagen Hair; RTK, Receptor Tyrosine Kinase; WS, Watson Syndrome.

Figure 2. Signaling pathways aberrantly regulated in NS vs. LS, and their respective targeted therapies

While the two syndromes share common phenotypic characteristics, NS- and LS-associated SHP2 differ in their biochemical properties. NS mutations result in increased phosphatase activity and, therefore, increase MAPK signaling. In contrast, LS mutations are loss-of-function mutations that lead to impaired agonist-evoked ERK activation but have concomitantly induce activity in several other signaling pathways including Akt/mTor, FAK, Stat and Jnk. This strongly favors the use of targeted therapies (PD0325901 and Rapamycin) based on the biochemical properties of these disorders. Positive regulation is indicated with a grey arrow, whereas negative regulation is indicated with a blunted arrow.