LEOPARD syndrome-associated SHP2 mutation confers leanness and protection from diet-induced obesity

Abstract

LEOPARD syndrome (multiple Lentigines, Electrocardiographic conduction abnormalities, Ocular hypertelorism, Pulmonary stenosis, Abnormal genitalia, Retardation of growth, sensorineural Deafness; LS), also called Noonan syndrome with multiple lentigines (NSML), is a rare autosomal dominant disorder associating various developmental defects, notably cardiopathies, dysmorphism, and short stature. It is mainly caused by mutations of the PTPN11 gene that catalytically inactivate the tyrosine phosphatase SHP2 (Src-homology 2 domain-containing phosphatase 2). Besides its pleiotropic roles during development, SHP2 plays key functions in energetic metabolism regulation. However, the metabolic outcomes of LS mutations have never been examined. Therefore, we performed an extensive metabolic exploration of an original LS mouse model, expressing the T468M mutation of SHP2, frequently borne by LS patients. Our results reveal that, besides expected symptoms, LS animals display a strong reduction of adiposity and resistance to diet-induced obesity, associated with overall better metabolic profile. We provide evidence that LS mutant expression impairs adipogenesis, triggers energy expenditure, and enhances insulin signaling, three features that can contribute to the lean phenotype of LS mice. Interestingly, chronic treatment of LS mice with low doses of MEK inhibitor, but not rapamycin, resulted in weight and adiposity gains. Importantly, preliminary data in a French cohort of LS patients suggests that most of them have lower-than-average body mass index, associated, for tested patients, with reduced adiposity. Altogether, these findings unravel previously unidentified characteristics for LS, which could represent a metabolic benefit for patients, but may also participate to the development or worsening of some traits of the disease. Beyond LS, they also highlight a protective role of SHP2 global LS-mimicking modulation toward the development of obesity and associated disorders.rasopathies | ras/MAPK | energy metabolism | adipose tissue

Elevated Ca2+transients and increased myofibrillar power generation cause cardiac hypercontractility in a model of Noonan syndrome with multiple lentigines

“…This mouse model recapitulates the aggressive form of HCM found in patients carrying the same SHP2 mutation. Importantly, all our prior findings in the Q510E-SHP2 model are consistent with the HCM phenotype described in other NSML models based on Y279C and T468M mutations in SHP2 (30,45). Because of the severity and early onset of the cardiac phenotype, the Q510E-SHP2 mouse model is ideally suited for proof-of-principle studies.…”

Growth patterns of patients with Noonan syndrome: correlation with age and genotype

“…Lower BMI values were also reported in children with NS by Malaquias et al (15) and, in line with these data, a survey showed that adults with NS rarely develop overweight or obesity (33). This suggested that NS-associated mutations could modify energy metabolism regulation, and this hypothesis has been recently confirmed in a mouse model expressing a NSML-PTPN11 (loss-of-function) mutation (34). NSML mice display a lean phenotype associating reduced adiposity with resistance to diet-induced obesity and improved carbohydrate metabolism, which could be converted by the inhibition of RAS/MAPK and PI3K signaling pathway activation, respectively.…”

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

“…Both NSML and NS mutations facilitate the open conformation and lead to enhanced interaction of SHP2 with binding partners, including cell membrane receptors and scaffolding adapters (20). However, whereas NS mutations are gain of function (GOF) and potentiate SHP2 phosphatase activity (21)(22)(23)(24)(25)(26), all NSML mutations identified so far affect conserved residues important for PTP catalysis and are loss of function (LOF) for the phosphatase activity (20,(27)(28)(29)(30).…”