PUBLICATION
Mutations in RIT1 cause Noonan syndrome - additional functional evidence and expanding the clinical phenotype
- Authors
- 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.
- ID
- ZDB-PUB-150512-7
- Date
- 2016
- Source
- Clinical genetics 89(3): 359-66 (Journal)
- Registered Authors
- Dallman, Julia
- Keywords
- Costello syndrome, Noonan syndrome, RASopathy, RIT1
- MeSH Terms
-
- Adolescent
- Animals
- Animals, Genetically Modified
- Child
- Child, Preschool
- Disease Models, Animal
- Eye Abnormalities/genetics
- Female
- Humans
- Infant
- Infant, Newborn
- Lower Extremity
- Lymphedema/genetics
- MAP Kinase Signaling System*
- Male
- Mutation, Missense*
- Noonan Syndrome/genetics
- Noonan Syndrome/metabolism*
- Protein Conformation
- Zebrafish/genetics
- ras Proteins/genetics*
- ras Proteins/metabolism
- PubMed
- 25959749 Full text @ Clin. Genet.
Citation
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. (2016) Mutations in RIT1 cause Noonan syndrome - additional functional evidence and expanding the clinical phenotype. Clinical genetics. 89(3):359-66.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping