Structural, Functional, and Clinical Characterization of a NovelPTPN11Mutation Cluster Underlying Noonan Syndrome

Abstract

Germline mutations in PTPN11, the gene encoding the Src-homology 2 (SH2) domain-containing protein tyrosine phosphatase (SHP2), cause Noonan syndrome (NS), a relatively common, clinically variable, multisystem disorder. Here, we report on the identification of five different PTPN11 missense changes affecting residues Leu , Leu , and Arg in 16 unrelated individuals with clinical diagnosis of NS or with features suggestive for this disorder, specifying a novel disease-causing mutation cluster. Expression of the mutant proteins in HEK293T cells documented their activating role on MAPK signaling. Structural data predicted a gain-of-function role of substitutions at residues Leu and Arg exerted by disruption of the N-SH2/PTP autoinhibitory interaction. Molecular dynamics simulations suggested a more complex behavior for changes affecting Leu , with possible impact on SHP2's catalytic activity/selectivity and proper interaction of the PTP domain with the regulatory SH2 domains. Consistent with that, biochemical data indicated that substitutions at codons 262 and 265 increased the catalytic activity of the phosphatase, while those affecting codon 261 were only moderately activating but impacted substrate specificity. Remarkably, these mutations underlie a relatively mild form of NS characterized by low prevalence of cardiac defects, short stature, and cognitive and behavioral issues, as well as less evident typical facial features.

Dermatological manifestations in Noonan syndrome: a prospective multicentric study of 129 patients positive for mutation

“…Our results confirm the relatively low frequency of significant dermatological manifestations in PTPN11 ‐NS, excluding PTPN11 ‐NSML, with the exception of easy bruising present in more than half the patients and are broadly comparable with previous findings of frequencies varying from 30% to 65% . Wavy or curly hair and temporal alopecia/scarce scalp hair were present in 23% and 15% of cases, respectively; this was similar to the previously reported frequency varying from 15% to 29% and 11% to 17%, respectively . Considering their relatively lower frequencies and the potentially significant changes in scalp hair characteristics during childhood and adolescence in NS, these hair abnormalities appear to be of little use for diagnosing NS.…”

“…Considering their relatively lower frequencies and the potentially significant changes in scalp hair characteristics during childhood and adolescence in NS, these hair abnormalities appear to be of little use for diagnosing NS. We observed KP in 18·5% of patients, which is a relatively higher frequency than 6% as previously reported, but not significant given that KP frequencies in children and adolescents in the general population vary from 2% to 26% …”

ClinGen’s RASopathy Expert Panel consensus methods for variant interpretation

“…At most one pathogenic allele at a given codon was observed in any population cohort with a minimum of 1000 individuals, 15, 17, 19 thus validating these MAF thresholds while recognizing that an occasional individual could be undiagnosed in the general population. Furthermore, a variant, PTPN11 p.Arg265Gln, presenting in patients with likely unrecognized mild phenotypic features 20 also fell below these conservative thresholds. These assessments concluded that a variant should be completely absent from large population cohorts for PM2 usage.…”

Cyclin D1 expression and novel mutational findings in Rosai‐Dorfman disease

“…Nonsense mutations are among the most common types of disease‐associated mutation involving NF1 , with mutations occurring around codon 1152 known to be pathogenic (Ars et al , ). Case 1 also harboured a PTPN11 mutation, which disrupts its autoinhibitory domain, leading to increased MAPK signaling (Pannone et al , ). This precise variant has been identified in the germline of patients with Noonan Syndrome.…”