Review articlePTPN11-Associated Mutations in the Heart: Has LEOPARD Changed Its RASpots?
Introduction
Congenital heart disorders (CHDs) are the most common type of birth defect (∼1/100 live births) and the major cause of birth-related deaths (Weismann and Gelb 2007). Abnormalities in signaling molecules and/or pathways are implicated in CHD pathogenesis; however, underlying mechanisms remain poorly understood and/or unknown. Recently, a new family of autosomal dominant syndromes was recognized, termed “RASopathies” (Figure 1). These disorders, which include LEOPARD syndrome (LS) (OMIM: 151100) and Noonan syndrome (NS) (OMIM: 163950), are caused by germline mutations in components of the RAS/RAF/MEK/ERK mitogen activating protein kinase (MAPK) pathway (Tidyman and Rauen 2009), which is required for normal cell growth, differentiation, and survival. Aberrant regulation of this pathway has profound effects, particularly on cardiac development, resulting in various abnormalities, including valvuloseptal defects and/or hypertrophic cardiomyopathy (HCM). With perturbations of the MAPK signaling pathway established as central to RASopathy disorders, several candidate genes along this canonical pathway have been identified in humans with RASopathy disease phenotypes, including mutations in KRAS, NRAS, SOS1, RAF1, BRAF, MEK1, MEK2, SHOC2, and CBL (Carta et al., 2006, Cirstea et al., 2010, Cordeddu et al., 2009, Dentici et al., 2009, Martinelli et al., 2010, Niihori et al., 2006, Pandit et al., 2007, Razzaque et al., 2007, Roberts et al., 2007, Schubbert et al., 2006, Tartaglia et al., 2007) (Figure 1). The gene most commonly mutated in NS and LS is PTPN11 (Figure 1) (Tartaglia et al. 2001).
Section snippets
PTPN11: Structure and Function
PTPN11 encodes the Src homology-2 (SH2) domain–containing nontransmembrane protein tyrosine phosphatase (PTP) SHP2. SHP2 is a ubiquitously expressed protein that contains two SH2 domains, a central PTP catalytic domain and a C-terminal tail with two tyrosine phosphorylation sites and a proline-rich motif. Resolution of the crystal structure, along with biochemical validation, has elucidated its mechanism of regulation, whereby in the inactive state, the backside loop of the N-SH2 domain folds
PTPN11 Mutations in Human Disease
SHP2 mutants have functional significance and, therefore, biological consequences. Heterozygous missense mutations in PTPN11 are observed in up to 90% of LS cases. LS, a rare autosomal dominant disorder, is an acronym for its presenting features of multiple lentigines, ECG conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormalities of genitalia, retardation of growth, and sensorineural deafness (Digilio et al., 2002, Legius et al., 2002) and is also referred to as Noonan
NS and LS: Differential Mechanisms of PTPN11 Regulation
Because NS and LS share such similar phenotypic characteristics in patients, they were considered to have similar disease pathogenesis. Interestingly, the point mutations identified in PTPN11 that were associated with NS were distinct from those associated with LS (Table 2). Indeed, the biochemical properties between the PTPN11 NS- and LS-specific point mutations are quite different (Hanna et al., 2006, Kontaridis et al., 2006, Tartaglia et al., 2006). Most NS mutations reside within the N-SH2
Modeling LS-Associated Cardiac Hypertrophy
Interestingly, initial in vivo studies reported conflicting results on the PTP function of the LS mutations in PTPN11. In contrast to the in vitro studies that provocatively suggested that LS mutations were LOF (Hanna et al., 2006, Kontaridis et al., 2006, Tartaglia et al., 2006), expression of the LS mutants Y279C or T468M in Drosophila resulted in ectopic wing veins and a rough eye phenotype, characteristics of increased ERK/MAPK activity in these tissues. In addition, genetic analysis of
Modeling NS-Associated Cardiac Hypertrophy
Biochemical, cell biological, and genetic evidence indicate that PTPN11 mutations associated with NS are hypermorphs that can enhance ERK/MAPK pathway activation (Keilhack et al. 2005). However, differing NS PTPN11 mutations appear to result in uniquely differing cardiac phenotypes (Araki et al., 2004, Araki et al., 2009, Krenz et al., 2008). For example, approximately 50% of the knockin mice for the Ptpn11 D61G NS exhibit valvuloseptal defects similar to those observed in NS patients but with
RASopathies: Future Therapeutic Intervention for NS and LS
Collectively, the results of these studies raise awareness for the need for treatment of diseases and disorders based on biochemical, rather than phenotypic, presentation. This provides further impetus to proceed with efforts to identify the other disease genes underlying these disorders and to generate animal models as well as human cell model systems. For example, the continued development of iPSC technology might enable a deeper understanding of the molecular mechanisms underlying human
Acknowledgments
This work was supported by National Institutes of Health grant HL088514, the Milton Fund, and the Beth Israel Deaconess Medical Center Division of Cardiology (to M.I.K.).
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