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.

中文翻译：

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努南综合征患者 PTPN11 变异的复合杂合性提供了对 SHP2 相关疾病机制的见解

RASopathies 是由影响参与 RAS-MAPK 信号级联的基因的突变引起的一系列临床相关疾病。其中，Noonan 综合征 (NS) 和 Noonan 综合征多斑痣 (NSML) 是主要与PTPN11显性突变相关的等位基因疾病，PTPN11编码非受体 SH2 结构域蛋白酪氨酸磷酸酶 SHP2。个别PTPN11突变特定于每种综合征，对催化产生相反的影响，但都支持 SHP2 与信号伙伴的相互作用。在这里，我们报告了一个在PTPN11 中含有双等位基因变体的 NS 受试者. 虽然前者 (p.Leu261Phe) 先前已在 NS 中报道过，但后者 (p.Thr357Met) 是一种损害催化作用的新变化。然而，携带 p.Thr357Met 的家族成员没有表现出任何适合 NSML 或在 RAS 病表型范围内的明显特征。这种变化对转录处理和蛋白质稳定性的主要影响被排除在外。这些发现进一步支持了 NSML 不能仅仅归因于 SHP2 催化活性受损的观点，并表明导致这种情况的PTPN11突变通过另一种显性机制起作用。