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Blood. 2019 Sep 27. pii: blood.2019001543. doi: 10.1182/blood.2019001543. [Epub ahead of print]

Catalytic dysregulation of SHP2 leading to Noonan syndromes impacts on platelet signaling and functions.

Author information

1
Inserm U1048 I2MC, France.
2
Laboratoire d'hématologie, CHU Toulouse, France.
3
Endocrinoloy, Bone diseases, and Genetics unit, Children Hospital, Toulouse University Hospital, France.
4
Laboratoire Hématologie, Centre Hospitalier Universitaire Toulouse, France.
5
Perlmutter Cancer Center, NYU Langone Medical Center, United States.
6
UMR1048, INSERM, France.
7
UMR 1048 Inserm-UPS, France.
8
University of Birmingham, United Kingdom.
9
The Medical School, Institute of Cardiovascular Sciences, University of Birmingham, United Kingdom.
10
Institute of Cardiovascular Sciences, University of Birmingham, United Kingdom.
11
Platelet production and function, signaling and phosphoinositides, INSERM, France.
12
INSERM U1048 I2MC, France sonia.severin@inserm.fr.

Abstract

SHP2, encoded by the PTPN11 gene, is a ubiquitous protein tyrosine phosphatase that is a critical regulator of signal transduction. Germline mutations in PTPN11 gene responsible for catalytic gain- or loss- of function of SHP2 cause two disorders with multiple organ defects, respectively Noonan syndrome (NS) and NS with Multiple Lentigines (NSML). Bleeding anomalies have been frequently reported in NS, but causes remain unclear. This study investigates platelet activation in patients with NS and NSML and in two mouse models carrying PTPN11 mutations responsible for these two syndromes. Platelets from NS mice and patients displayed a significant reduction in aggregation induced by low concentrations of GPVI and CLEC-2 agonists, and a decrease in thrombus growth on a collagen surface under arterial shear stress. This was associated with deficiencies in GPVI and aIIbb3 integrin signaling, platelet secretion and TXA2 generation. Similarly, arterial thrombus formation was significantly reduced in response to a local carotid injury in NS mice associated with a significant increase in the tail bleeding time. In contrast, NSML mice platelets exhibited increased platelet activation following GPVI and CLEC-2 stimulation and enhanced platelet thrombotic phenotype on collagen matrix under shear stress. Blood samples from NSML patients also showed a shear stress-dependent elevation of platelet responses on collagen matrix. This study brings new insights into the understanding of SHP2 function in platelets, points to new thrombopathies linked to platelet signaling defects and provides important information for the medical care of patients with NS in situations at risk of bleeding.

PMID:
31562133
DOI:
10.1182/blood.2019001543

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