PTPN11 (Shp2) Mutations in LEOPARD Syndrome Have Dominant Negative, Not Activating, Effects

Abstract

Multiple lentigines/LEOPARD syndrome (LS) is a rare, autosomal dominant disorder characterized by Lentigines, Electrocardiogram abnormalities, Ocular hypertelorism, Pulmonic valvular stenosis, Abnormalities of genitalia, Retardation of growth, and Deafness. Like the more common Noonan syndrome (NS), LS is caused by germ line missense mutations in PTPN11, encoding the protein-tyrosine phosphatase Shp2. Enzymologic, structural, cell biological, and mouse genetic studies indicate that NS is caused by gain-of-function PTPN11 mutations. Because NS and LS share several features, LS has been viewed as an NS variant. We examined a panel of LS mutants, including the two most common alleles. Surprisingly, we found that in marked contrast to NS, LS mutants are catalytically defective and act as dominant negative mutations that interfere with growth factor/Erk-mitogen-activated protein kinasemediated signaling. Molecular modeling and biochemical studies suggest that LS mutations contort the Shp2 catalytic domain and result in open, inactive forms of Shp2. Our results establish that the pathogenesis of LS and NS is distinct and suggest that these disorders should be distinguished by mutational analysis rather than clinical presentation.

Protein tyrosine phosphatase activity in the neural crest is essential for normal heart and skull development

“…SHP2 mutations in LS are clustered in the PTP domain and lead to decreased SHP2 activity. LS alleles exhibit substantial ERK1/2 activation in vitro (5,36), consistent with our observations in the SHP2-ablated NCCs. We first hypothesized that a SHP2 null in NCCs might mimic some aspects of LS; unexpectedly, however, the mice more closely phenocopied the 22q11 deletion syndrome.…”

“…Affected patients present with several overlapping phenotypes in the brain, heart, face, and skin; thus, these syndromes are termed neurocardiofacial cutaneous (NCFC) syndromes (4). Mutations associated with these syndromes often result in gain of function with respect to signaling through ERK1/2, with the exception of certain LEOPARD syndrome (LS) mutations in PTPN11 associated with loss of function (5,6).…”

MAP3Ks as central regulators of cell fate during development

“…Shp2 regulates MEKK3 and MEKK4 activities (Lerner-Marmarosh et al, 2003;Halfter et al, 2005). Of interest, mutations in Shp2 are a leading cause of Noonan's syndrome and Leopard syndrome, which are characterized by craniofacial, skeletal, cardiac developmental defects and myeloproliferative disorders (Tartaglia et al, 2001;Legius et al, 2002;Araki et al, 2004;Kontaridis et al, 2006). Additional work will determine the significance of Shp2/ MEKK3 and Shp2/MEKK4 interactions in development.…”

MKK signaling and vascularization

“…Recently, mutations in genes linked to MKK signaling have been associated with a group of human syndromes that includes cardiofacio-cutaneous (CFC) syndrome (mutations in KRas, MEK1, MEK2 and BRAF) (Niihori et al, 2006;Rodriguez-Viciana et al, 2006), Noonan syndrome (NS) and LEOPARD syndrome (LS), which are caused by gain-of-function mutations and inactivating mutations in the protein tyrosine phosphatase PTP11 (SHP2), leading to constitutive (Araki et al, 2004;Fragale et al, 2004) or impaired MAPK activation (Kontaridis et al, 2005), respectively, as well as Costello syndrome (CS), an autosomal dominant disease that has been linked to activating mutations in HRAS (Aoki et al, 2005;Estep et al, 2006). Each causes a similar array of phenotypic consequences including facial dysmorphia, abnormal growth and, notably in this context, cardiovascular defects.…”