Compound heterozygosity for PTPN11 variants in a subject with Noonan syndrome provides insights into the mechanism of SHP2‐related disorders. Issue 3 (4th January 2021)

• Record Type: Journal Article
• Authors: Lorca, Rebeca; Pannone, Luca; Cuesta‐Llavona, Elías; Bocchinfuso, Gianfranco; Rodríguez‐Reguero, Julian; Carpentieri, Giovanna; Hernando, Inés; Flex, Elisabetta; Tartaglia, Marco; Coto, Eliecer; Gómez, Juan; Martinelli, Simone
• Is Part Of: Clinical genetics. Volume 99:Issue 3(2021)
• Page Start: 457
• Page End: 461
• Publication Date: 2021-01-04
• Subjects: LEOPARD syndrome -- Noonan syndrome -- phosphatase assay -- PTPN11 -- SHP2; Medical genetics -- Periodicals; 616.0420
• DOI: 10.1111/cge.13904
• Languages: English
• ISSNs: 0009-9163

Abstract

Abstract: The RASopathies are a family of clinically related disorders caused by mutations affecting genes participating in the RAS‐MAPK signaling cascade. Among them, Noonan syndrome (NS) and Noonan syndrome with multiple lentigines (NSML) are allelic conditions principally associated with dominant mutations in PTPN11, which encodes the nonreceptor SH2 domain‐containing protein tyrosine phosphatase SHP2. Individual PTPN11 mutations are specific to each syndrome and have opposite consequences on catalysis, but all favor SHP2's interaction with signaling partners. Here, we report on a subject with NS harboring biallelic variants in PTPN11 . While the former (p.Leu261Phe) had previously been reported in NS, the latter (p.Thr357Met) is a novel change impairing catalysis. Members of the family carrying p.Thr357Met, however, did not show any obvious feature fitting NSML or within the RASopathy phenotypic spectrum. A major impact of this change on transcript processing and protein stability was excluded. These findings further support the view that NSML cannot be ascribed merely to impaired SHP2's catalytic activity and suggest that PTPN11 mutations causing this condition act through an alternative dominant mechanism. Abstract :