Naslov
Mutations inRIT1cause Noonan syndrome - additional functional evidence and expanding the clinical phenotype

Autori
Koenighofer, M. ; Hung, C. Y. ; McCauley, J. L. ; Dallman, J. ; Back, E. J. ; Mihalek, I. ; Gripp, K. W. ; Sol-Church, K. ; Rusconi, P. ; Zhang, Z. ; Shi, G-X. ; Andres, D. A. ; Bodamer, O. A.

Izvornik
Clinical Genetics (0009-9163) 89 (2015), 3; 359-366

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
RIT1, Noonan syndrom, genotype-phenotype correlation

Sažetak
RASopathies are a clinically heterogeneous group of conditions caused by mutations in 1 of 16 proteins in the RAS‐mitogen activated protein kinase (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.

Izvorni jezik
Engleski

Znanstvena područja
Biologija, Biotehnologija u biomedicini (prirodno područje, biomedicina i zdravstvo, biotehničko područje)

POVEZANOST RADA