Unidad de Referencia de Cardiopatías Familiares-HUCA, Hospital Universitario Central de Asturias (HUCA) - Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain.
Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.
Clin Genet. 2021 Mar;99(3):457-461. doi: 10.1111/cge.13904. Epub 2021 Jan 4.
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.
RAS 相关疾病是一组具有临床相关性的疾病，由影响参与 RAS-MAPK 信号级联反应的基因的突变引起。其中，努南综合征（NS）和多发性黑子综合征（NSML）是主要与编码非受体 SH2 结构域的含酪氨酸磷酸酶 SHP2 的 PTPN11 基因的显性突变相关的等位基因疾病。个别 PTPN11 突变是每种综合征所特有的，对催化具有相反的影响，但都有利于 SHP2 与信号伙伴的相互作用。在这里，我们报告了一个 NS 患者携带 PTPN11 的双等位基因变异。虽然前者（p.Leu261Phe）以前曾在 NS 中报道过，但后者（p.Thr357Met）是一种新的改变，会损害催化作用。携带 p.Thr357Met 的家族成员没有表现出任何符合 NSML 或 RAS 相关疾病表型谱的明显特征。这种变化对转录处理和蛋白质稳定性的重大影响被排除在外。这些发现进一步支持了这样一种观点，即 NSML 不能仅仅归因于 SHP2 催化活性的受损，并且表明导致这种情况的 PTPN11 突变通过另一种显性机制起作用。
