LymphedemaV1, Main, Exploration, bibRecord, 001A72

Mutations in RIT1 cause Noonan syndrome – additional functional evidence and expanding the clinical phenotype

Identifieur interne : 001A72 ( Main/Exploration ); précédent : 001A71; suivant : 001A73

Mutations in RIT1 cause Noonan syndrome – additional functional evidence and expanding the clinical phenotype

Auteurs : Martin Koenighofer [Autriche] ; Christina Y. Hung [États-Unis] ; Jacob L. Mccauley [États-Unis] ; Julia Dallman [États-Unis] ; Emma J. Back [États-Unis] ; Ivana Mihalek [Singapour] ; Karen W. Gripp [États-Unis] ; Katia Sol-Church [États-Unis] ; Paolo Rusconi [États-Unis] ; Zhaiyi Zhang [États-Unis] ; Geng-Xian Shi [États-Unis] ; Douglas A. Andres [États-Unis] ; Olaf A. Bodamer [États-Unis]

Source :

Clinical genetics [ 0009-9163 ] ; 2015.

RBID : PMC:4760689

Descripteurs français

English descriptors

KwdEn :
- 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).
MESH :
- chemical , genetics : ras Proteins.
- genetics : Eye Abnormalities, Lymphedema, Noonan Syndrome, Zebrafish.
- metabolism : Noonan Syndrome, ras Proteins.
- Adolescent, Animals, Animals, Genetically Modified, Child, Child, Preschool, Disease Models, Animal, Female, Humans, Infant, Infant, Newborn, Lower Extremity, MAP Kinase Signaling System, Male, Mutation, Missense, Protein Conformation.

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.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4760689

DOI: 10.1111/cge.12608
PubMed: 25959749
PubMed Central: 4760689

Affiliations:

Autriche, Singapour, États-Unis

Le document en format XML

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<front><div type="abstract" xml:lang="en"><p id="P1">RASopathies are a clinically heterogeneous group of conditions caused by mutations in one of sixteen proteins in the RAS-MAPK pathway. Recently, mutations in <italic>RIT1</italic>
 were identified as a novel cause for Noonan syndrome. Here we provide additional functional evidence for a causal role of <italic>RIT1</italic>
 mutations and expand the associated phenotypic spectrum.</p>
<p id="P2">We identified two <italic>de novo</italic>
 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 <italic>RIT1</italic>
 for spatial and temporal organization of the growing organism. In addition, we observed severe lymphedema of the lower extremity and genitalia in one patient.</p>
<p id="P3">We provide additional evidence for a causal relationship between pathogenic mutations in <italic>RIT1</italic>
, 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.</p>
</div>
</front>
</TEI>
<affiliations><list><country><li>Autriche</li>
<li>Singapour</li>
<li>États-Unis</li>
</country>
</list>
<tree><country name="Autriche"><noRegion><name sortKey="Koenighofer, Martin" sort="Koenighofer, Martin" uniqKey="Koenighofer M" first="Martin" last="Koenighofer">Martin Koenighofer</name>
</noRegion>
</country>
<country name="États-Unis"><noRegion><name sortKey="Hung, Christina Y" sort="Hung, Christina Y" uniqKey="Hung C" first="Christina Y." last="Hung">Christina Y. Hung</name>
</noRegion>
<name sortKey="Andres, Douglas A" sort="Andres, Douglas A" uniqKey="Andres D" first="Douglas A." last="Andres">Douglas A. Andres</name>
<name sortKey="Back, Emma J" sort="Back, Emma J" uniqKey="Back E" first="Emma J." last="Back">Emma J. Back</name>
<name sortKey="Bodamer, Olaf A" sort="Bodamer, Olaf A" uniqKey="Bodamer O" first="Olaf A." last="Bodamer">Olaf A. Bodamer</name>
<name sortKey="Bodamer, Olaf A" sort="Bodamer, Olaf A" uniqKey="Bodamer O" first="Olaf A." last="Bodamer">Olaf A. Bodamer</name>
<name sortKey="Dallman, Julia" sort="Dallman, Julia" uniqKey="Dallman J" first="Julia" last="Dallman">Julia Dallman</name>
<name sortKey="Gripp, Karen W" sort="Gripp, Karen W" uniqKey="Gripp K" first="Karen W." last="Gripp">Karen W. Gripp</name>
<name sortKey="Mccauley, Jacob L" sort="Mccauley, Jacob L" uniqKey="Mccauley J" first="Jacob L." last="Mccauley">Jacob L. Mccauley</name>
<name sortKey="Rusconi, Paolo" sort="Rusconi, Paolo" uniqKey="Rusconi P" first="Paolo" last="Rusconi">Paolo Rusconi</name>
<name sortKey="Shi, Geng Xian" sort="Shi, Geng Xian" uniqKey="Shi G" first="Geng-Xian" last="Shi">Geng-Xian Shi</name>
<name sortKey="Sol Church, Katia" sort="Sol Church, Katia" uniqKey="Sol Church K" first="Katia" last="Sol-Church">Katia Sol-Church</name>
<name sortKey="Zhang, Zhaiyi" sort="Zhang, Zhaiyi" uniqKey="Zhang Z" first="Zhaiyi" last="Zhang">Zhaiyi Zhang</name>
</country>
<country name="Singapour"><noRegion><name sortKey="Mihalek, Ivana" sort="Mihalek, Ivana" uniqKey="Mihalek I" first="Ivana" last="Mihalek">Ivana Mihalek</name>
</noRegion>
</country>
</tree>
</affiliations>
</record>

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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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