LymphedemaV1, PubMed, Checkpoint, bibRecord, 000755

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

Identifieur interne : 000755 ( PubMed/Checkpoint ); précédent : 000754; suivant : 000756

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

Auteurs : M. Koenighofer [Autriche] ; C Y Hung [États-Unis] ; J L Mccauley [États-Unis] ; J. Dallman [États-Unis] ; E J Back [États-Unis] ; I. Mihalek [Singapour] ; K W Gripp [États-Unis] ; K. Sol-Church [États-Unis] ; P. Rusconi [États-Unis] ; Z. Zhang [États-Unis] ; G-X Shi [États-Unis] ; D A Andres [États-Unis] ; O A Bodamer [États-Unis]

Source :

Clinical genetics [ 1399-0004 ] ; 2016.

RBID : pubmed:25959749

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 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.

DOI: 10.1111/cge.12608
PubMed: 25959749

Affiliations:

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<term>Membre inférieur</term>
<term>Modèles animaux de maladie humaine</term>
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<term>Protéines G ras</term>
<term>Syndrome de Noonan</term>
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<front><div type="abstract" xml:lang="en">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.</div>
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<Title>Clinical genetics</Title>
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<Abstract><AbstractText>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.</AbstractText>
<CopyrightInformation>© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.</CopyrightInformation>
</Abstract>
<AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Koenighofer</LastName>
<ForeName>M</ForeName>
<Initials>M</Initials>
<AffiliationInfo><Affiliation>Department of Otorhinolaryngology, Medical University of Vienna, Vienna, Austria.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Hung</LastName>
<ForeName>C Y</ForeName>
<Initials>CY</Initials>
<AffiliationInfo><Affiliation>Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Dr. John T. Macdonald Foundation Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, FL, USA.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Harvard Medical School, Boston, MA, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>McCauley</LastName>
<ForeName>J L</ForeName>
<Initials>JL</Initials>
<AffiliationInfo><Affiliation>Dr. John T. Macdonald Foundation Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, FL, USA.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Dallman</LastName>
<ForeName>J</ForeName>
<Initials>J</Initials>
<AffiliationInfo><Affiliation>Department of Biology, University of Miami, Miami, FL, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Back</LastName>
<ForeName>E J</ForeName>
<Initials>EJ</Initials>
<AffiliationInfo><Affiliation>Department of Biology, University of Miami, Miami, FL, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Mihalek</LastName>
<ForeName>I</ForeName>
<Initials>I</Initials>
<AffiliationInfo><Affiliation>Bioinformatics Institute A*STAR Singapore, Singapore.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Gripp</LastName>
<ForeName>K W</ForeName>
<Initials>KW</Initials>
<AffiliationInfo><Affiliation>Division of Medical Genetics, Alfred I. duPont Hospital for Children, Wilmington, DE, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Sol-Church</LastName>
<ForeName>K</ForeName>
<Initials>K</Initials>
<AffiliationInfo><Affiliation>Department of Pediatrics, Division of Pediatric Cardiology, Miller School of Medicine, University of Miami, Miami, FL, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Rusconi</LastName>
<ForeName>P</ForeName>
<Initials>P</Initials>
<AffiliationInfo><Affiliation>Department of Pediatrics, Division of Pediatric Cardiology, Miller School of Medicine, University of Miami, Miami, FL, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Zhang</LastName>
<ForeName>Z</ForeName>
<Initials>Z</Initials>
<AffiliationInfo><Affiliation>Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Shi</LastName>
<ForeName>G-X</ForeName>
<Initials>GX</Initials>
<AffiliationInfo><Affiliation>Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Andres</LastName>
<ForeName>D A</ForeName>
<Initials>DA</Initials>
<AffiliationInfo><Affiliation>Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Bodamer</LastName>
<ForeName>O A</ForeName>
<Initials>OA</Initials>
<AffiliationInfo><Affiliation>Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Harvard Medical School, Boston, MA, USA.</Affiliation>
</AffiliationInfo>
</Author>
</AuthorList>
<Language>eng</Language>
<GrantList CompleteYN="Y"><Grant><GrantID>NS045103</GrantID>
<Acronym>NS</Acronym>
<Agency>NINDS NIH HHS</Agency>
<Country>United States</Country>
</Grant>
<Grant><GrantID>P20 GM103464</GrantID>
<Acronym>GM</Acronym>
<Agency>NIGMS NIH HHS</Agency>
<Country>United States</Country>
</Grant>
<Grant><GrantID>P20GM103446</GrantID>
<Acronym>GM</Acronym>
<Agency>NIGMS NIH HHS</Agency>
<Country>United States</Country>
</Grant>
<Grant><GrantID>P20 RR020173</GrantID>
<Acronym>RR</Acronym>
<Agency>NCRR NIH HHS</Agency>
<Country>United States</Country>
</Grant>
<Grant><GrantID>P20 GM103446</GrantID>
<Acronym>GM</Acronym>
<Agency>NIGMS NIH HHS</Agency>
<Country>United States</Country>
</Grant>
<Grant><GrantID>R56 NS045103</GrantID>
<Acronym>NS</Acronym>
<Agency>NINDS NIH HHS</Agency>
<Country>United States</Country>
</Grant>
<Grant><GrantID>P20GM103464</GrantID>
<Acronym>GM</Acronym>
<Agency>NIGMS NIH HHS</Agency>
<Country>United States</Country>
</Grant>
<Grant><GrantID>R01 NS045103</GrantID>
<Acronym>NS</Acronym>
<Agency>NINDS NIH HHS</Agency>
<Country>United States</Country>
</Grant>
</GrantList>
<PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType>
<PublicationType UI="D052061">Research Support, N.I.H., Extramural</PublicationType>
<PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType>
</PublicationTypeList>
<ArticleDate DateType="Electronic"><Year>2015</Year>
<Month>06</Month>
<Day>04</Day>
</ArticleDate>
</Article>
<MedlineJournalInfo><Country>Denmark</Country>
<MedlineTA>Clin Genet</MedlineTA>
<NlmUniqueID>0253664</NlmUniqueID>
<ISSNLinking>0009-9163</ISSNLinking>
</MedlineJournalInfo>
<ChemicalList><Chemical><RegistryNumber>EC 3.6.1.-</RegistryNumber>
<NameOfSubstance UI="C486776">RIT1 protein, human</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>EC 3.6.5.2</RegistryNumber>
<NameOfSubstance UI="D018631">ras Proteins</NameOfSubstance>
</Chemical>
</ChemicalList>
<CitationSubset>IM</CitationSubset>
<CommentsCorrectionsList><CommentsCorrections RefType="Cites"><RefSource>Proc Natl Acad Sci U S A. 2014 Aug 5;111(31):11473-8</RefSource>
<PMID Version="1">25049390</PMID>
</CommentsCorrections>
<CommentsCorrections RefType="Cites"><RefSource>Mol Biol Cell. 2011 Sep;22(17):3231-41</RefSource>
<PMID Version="1">21737674</PMID>
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<PMID Version="1">21263000</PMID>
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<CommentsCorrections RefType="Cites"><RefSource>Am J Med Genet A. 2014 Sep;164A(9):2310-6</RefSource>
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</CommentsCorrections>
<CommentsCorrections RefType="Cites"><RefSource>J Neurosci. 1996 Nov 1;16(21):6784-94</RefSource>
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<CommentsCorrections RefType="Cites"><RefSource>Dis Model Mech. 2012 Jul;5(4):546-52</RefSource>
<PMID Version="1">22301711</PMID>
</CommentsCorrections>
<CommentsCorrections RefType="Cites"><RefSource>J Med Genet. 2015 Jun;52(6):413-21</RefSource>
<PMID Version="1">25795793</PMID>
</CommentsCorrections>
<CommentsCorrections RefType="Cites"><RefSource>Am J Med Genet A. 2014 Nov;164A(11):2952-7</RefSource>
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<CommentsCorrections RefType="Cites"><RefSource>Front Neurosci. 2011 Mar 16;5:35</RefSource>
<PMID Version="1">21441990</PMID>
</CommentsCorrections>
<CommentsCorrections RefType="Cites"><RefSource>Pediatrics. 2014 Oct;134(4):e1149-62</RefSource>
<PMID Version="1">25180280</PMID>
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<CommentsCorrections RefType="Cites"><RefSource>Am J Hum Genet. 2013 Jul 11;93(1):173-80</RefSource>
<PMID Version="1">23791108</PMID>
</CommentsCorrections>
</CommentsCorrectionsList>
<MeshHeadingList><MeshHeading><DescriptorName UI="D000293" MajorTopicYN="N">Adolescent</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D030801" MajorTopicYN="N">Animals, Genetically Modified</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D002648" MajorTopicYN="N">Child</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D002675" MajorTopicYN="N">Child, Preschool</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D004195" MajorTopicYN="N">Disease Models, Animal</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D005124" MajorTopicYN="N">Eye Abnormalities</DescriptorName>
<QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D005260" MajorTopicYN="N">Female</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D007223" MajorTopicYN="N">Infant</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D007231" MajorTopicYN="N">Infant, Newborn</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D035002" MajorTopicYN="N">Lower Extremity</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D008209" MajorTopicYN="N">Lymphedema</DescriptorName>
<QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D020935" MajorTopicYN="Y">MAP Kinase Signaling System</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D008297" MajorTopicYN="N">Male</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D020125" MajorTopicYN="Y">Mutation, Missense</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D009634" MajorTopicYN="N">Noonan Syndrome</DescriptorName>
<QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D011487" MajorTopicYN="N">Protein Conformation</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D015027" MajorTopicYN="N">Zebrafish</DescriptorName>
<QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D018631" MajorTopicYN="N">ras Proteins</DescriptorName>
<QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
</MeshHeading>
</MeshHeadingList>
<OtherID Source="NLM">NIHMS694165 [Available on 03/01/17]</OtherID>
<OtherID Source="NLM">PMC4760689 [Available on 03/01/17]</OtherID>
<KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">Costello syndrome</Keyword>
<Keyword MajorTopicYN="N">Noonan syndrome</Keyword>
<Keyword MajorTopicYN="N">RASopathy</Keyword>
<Keyword MajorTopicYN="N">RIT1</Keyword>
</KeywordList>
</MedlineCitation>
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<Month>04</Month>
<Day>05</Day>
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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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