Mutations in RIT1 cause Noonan syndrome - additional functional evidence and expanding the clinical phenotype.
Mutations in RIT1 cause Noonan syndrome - additional functional evidence and expanding the clinical phenotype.
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DOI：
10.1111/cge.12608
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发表时间：
2016-03
影响因子：
3.5
通讯作者：
Bodamer OA
中科院分区：
文献类型：
--
作者：
Koenighofer M;Hung CY;McCauley JL;Dallman J;Back EJ;Mihalek I;Gripp KW;Sol-Church K;Rusconi P;Zhang Z;Shi GX;Andres DA;Bodamer OA
ras病是一种临床异质性的疾病，由RAS-MAPK通路中16种蛋白质中的一种突变引起。最近，RIT1突变被确定为Noonan综合征的新病因。在这里，我们为RIT1突变的因果作用提供了额外的功能证据，并扩展了相关的表型谱。我们发现了两个新的错义变体p.Met90Ile和p.Ala57Gly。与野生型相比，这两种变异都导致MEK-ERK信号的增加，强调功能获得是主要的功能机制。将p.Met90Ile和p.Ala57Gly引入斑马鱼胚胎，不仅再现了人类表型的各个方面，而且揭示了眼睛发育的异常，强调了RIT1对生长生物体的时空组织的重要性。此外，我们观察到一个病人的下肢和生殖器严重淋巴水肿。我们为RIT1致病性突变、RAS-MAPK/MEK-ERK信号的增加和临床表型之间的因果关系提供了额外的证据。突变的RIT1蛋白可能具有GTPase活性降低或与细胞GTPase激活蛋白相互作用的能力减弱，但其确切机制尚不清楚。其表型谱可能扩大，除颈部水肿外，还包括下肢淋巴水肿。
RASopathies are a clinically heterogeneous group of conditions caused by mutations in one of sixteen proteins in the RAS-MAPK pathway. Recently, mutations in RIT1 were identified as a novel cause for Noonan syndrome. Here we provide additional functional evidence for a causal role of RIT1 mutations and expand the associated phenotypic spectrum. We identified two de novo missense variants p.Met90Ile and, p.Ala57Gly. Both variants resulted in increased MEK-ERK signaling compared to wild-type, underscoring gain-of-function as the primary functional mechanism. Introduction of p.Met90Ile and p.Ala57Gly into zebrafish embryos reproduced not only aspects of the human phenotype but also revealed abnormalities of eye development, emphasizing the importance of RIT1 for spatial and temporal organization of the growing organism. In addition, we observed severe lymphedema of the lower extremity and genitalia in one patient. We provide additional evidence for a causal relationship between pathogenic mutations in RIT1, increased RAS-MAPK/MEK-ERK signaling and the clinical phenotype. The mutant RIT1 protein may possess reduced GTPase activity or a diminished ability to interact with cellular GTPase activating proteins, however the precise mechanism remains unknown. The phenotypic spectrum is likely to expand and includes lymphedema of the lower extremities in addition to nuchal hygroma.