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Compound heterozygosity for PTPN11 variants in a subject with Noonan syndrome provides insights into the mechanism of SHP2 ‐related disorders
Author(s) -
Lorca Rebeca,
Pan Luca,
CuestaLlavona Elías,
Bocchinfuso Gianfranco,
RodríguezReguero Julian,
Carpentieri Giovanna,
Hernando Inés,
Flex Elisabetta,
Tartaglia Marco,
Coto Eliecer,
Gómez Juan,
Martinelli Simone
Publication year - 2021
Publication title -
clinical genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.543
H-Index - 102
eISSN - 1399-0004
pISSN - 0009-9163
DOI - 10.1111/cge.13904
Subject(s) - ptpn11 , noonan syndrome , genetics , phenotype , loss of heterozygosity , protein tyrosine phosphatase , biology , mutation , mapk/erk pathway , allele , costello syndrome , gene , cancer research , signal transduction , kras
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.