Recessive primary congenital lymphoedema caused by a VEGFR3 mutation
Identifieur interne : 006547 ( Main/Exploration ); précédent : 006546; suivant : 006548Recessive primary congenital lymphoedema caused by a VEGFR3 mutation
Auteurs : A. Ghalamkarpour [Belgique] ; W. Holnthoner [Finlande] ; P. Saharinen [Finlande] ; L M Boon [Belgique] ; J B Mulliken [États-Unis] ; Kari Alitalo [Finlande] ; M. Vikkula [Belgique]Source :
- Journal of Medical Genetics [ 0022-2593 ] ; 2009-06.
Descripteurs français
- KwdFr :
- Alignement de séquences, Données de séquences moléculaires, Gènes récessifs, Humains, Lignée cellulaire, Lymphoedème (), Lymphoedème (génétique), Microscopie de fluorescence, Mutation, Pedigree, Récepteur-3 au facteur croissance endothéliale vasculaire (), Récepteur-3 au facteur croissance endothéliale vasculaire (génétique), Récepteur-3 au facteur croissance endothéliale vasculaire (métabolisme), Substitution d'acide aminé, Séquence d'acides aminés, Transduction du signal.
- MESH :
- génétique : Lymphoedème, Récepteur-3 au facteur croissance endothéliale vasculaire.
- métabolisme : Récepteur-3 au facteur croissance endothéliale vasculaire.
- Alignement de séquences, Données de séquences moléculaires, Gènes récessifs, Humains, Lignée cellulaire, Lymphoedème, Microscopie de fluorescence, Mutation, Pedigree, Récepteur-3 au facteur croissance endothéliale vasculaire, Substitution d'acide aminé, Séquence d'acides aminés, Transduction du signal.
- Pascal (Inist)
- Wicri :
English descriptors
- KwdEn :
- Amino Acid Sequence, Amino Acid Substitution, Cell Line, Congenital, Genes, Recessive, Genetic disease, Genetics, Human, Humans, Lymphedema, Lymphedema (congenital), Lymphedema (genetics), Microscopy, Fluorescence, Molecular Sequence Data, Mutation, Pedigree, Recessive character, Sequence Alignment, Signal Transduction, Vascular Endothelial Growth Factor Receptor-3 (chemistry), Vascular Endothelial Growth Factor Receptor-3 (genetics), Vascular Endothelial Growth Factor Receptor-3 (metabolism).
- MESH :
- chemical , chemistry : Vascular Endothelial Growth Factor Receptor-3.
- congenital : Lymphedema.
- genetics : Lymphedema, Vascular Endothelial Growth Factor Receptor-3.
- chemical , metabolism : Vascular Endothelial Growth Factor Receptor-3.
- Amino Acid Sequence, Amino Acid Substitution, Cell Line, Genes, Recessive, Humans, Microscopy, Fluorescence, Molecular Sequence Data, Mutation, Pedigree, Sequence Alignment, Signal Transduction.
Abstract
Background: Heterozygous mutations in VEGFR3 have been identified in some familial cases with dominantly inherited primary congenital lymphoedema, known as Nonne–Milroy disease. Recessive cases of primary lymphoedema with a genetic cause are not known, except for two families with syndromic hypotrichosis–lymphoedema–telangiectasia, with a SOX18 mutation. Methods and results: In this study, we present the first case of isolated primary congenital lymphoedema with recessive inheritance, caused by a homozygous mutation in VEGFR3. The novel mutation is a transition from alanine-to-threonine in amino acid 855, located in the ATP binding domain of the VEGFR3 receptor. Assessment of receptor function showed impaired ligand induced internalisation and ERK1/2 activity. Moreover, receptor phosphorylation was reduced, although less so than for a kinase-dead VEGFR3 mutation, which causes Nonne–Milroy disease. Conclusion: A hypomorphic VEGFR3 mutation, with moderate effect on receptor function, in a homozygous state can result in insufficient lymphatic functioning. Thus, in addition to Nonne–Milroy disease with dominant inheritance, VEGFR3 alterations can cause isolated recessive primary congenital lymphoedema. These data expand our understanding of the aetiology of congenital lymphoedema and suggest that large scale screening of VEGFR3 in all primary lymphoedema patients is necessary.
Url:
DOI: 10.1136/jmg.2008.064469
Affiliations:
- Belgique, Finlande, États-Unis
- Massachusetts, Région de Bruxelles-Capitale, Uusimaa
- Bruxelles, Helsinki, Louvain-la-Neuve
- Université catholique de Louvain, Université d'Helsinki
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Ghalamkarpour</name><affiliation wicri:level="4"><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Human Molecular Genetics, de Duve Institute, Université catholique de Louvain, Brussels</wicri:regionArea><placeName><settlement type="city">Bruxelles</settlement><region nuts="2">Région de Bruxelles-Capitale</region><settlement type="city">Louvain-la-Neuve</settlement></placeName><orgName type="university">Université catholique de Louvain</orgName></affiliation></author><author><name sortKey="Holnthoner, W" sort="Holnthoner, W" uniqKey="Holnthoner W" first="W" last="Holnthoner">W. Holnthoner</name><affiliation wicri:level="1"><country xml:lang="fr">Finlande</country><wicri:regionArea>Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Biomedicum Helsinki, Haartman Institute and Helsinki University Central Hospital, University of Helsinki, Helsinki</wicri:regionArea><wicri:noRegion>Helsinki</wicri:noRegion></affiliation></author><author><name sortKey="Saharinen, P" sort="Saharinen, P" uniqKey="Saharinen P" first="P" last="Saharinen">P. Saharinen</name><affiliation wicri:level="1"><country xml:lang="fr">Finlande</country><wicri:regionArea>Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Biomedicum Helsinki, Haartman Institute and Helsinki University Central Hospital, University of Helsinki, Helsinki</wicri:regionArea><wicri:noRegion>Helsinki</wicri:noRegion></affiliation></author><author><name sortKey="Boon, L M" sort="Boon, L M" uniqKey="Boon L" first="L M" last="Boon">L M Boon</name><affiliation wicri:level="4"><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Human Molecular Genetics, de Duve Institute, Université catholique de Louvain, Brussels</wicri:regionArea><placeName><settlement type="city">Bruxelles</settlement><region nuts="2">Région de Bruxelles-Capitale</region><settlement type="city">Louvain-la-Neuve</settlement></placeName><orgName type="university">Université catholique de Louvain</orgName></affiliation><affiliation wicri:level="3"><country xml:lang="fr">Belgique</country><wicri:regionArea>Center for Vascular Anomalies, Division of Plastic Surgery, Cliniques Universitaires Saint-Luc and Université catholique de Louvain, Brussels</wicri:regionArea><placeName><settlement type="city">Bruxelles</settlement><region nuts="2">Région de Bruxelles-Capitale</region></placeName></affiliation></author><author><name sortKey="Mulliken, J B" sort="Mulliken, J B" uniqKey="Mulliken J" first="J B" last="Mulliken">J B Mulliken</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Vascular Anomalies Center, Department of Plastic Surgery, Children’s Hospital, Harvard Medical School, Boston, Massachusetts</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Alitalo, K" sort="Alitalo, K" uniqKey="Alitalo K" first="K" last="Alitalo">Kari Alitalo</name><affiliation wicri:level="1"><country xml:lang="fr">Finlande</country><wicri:regionArea>Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Biomedicum Helsinki, Haartman Institute and Helsinki University Central Hospital, University of Helsinki, Helsinki</wicri:regionArea><wicri:noRegion>Helsinki</wicri:noRegion><placeName><settlement type="city">Helsinki</settlement><region type="région" nuts="2">Uusimaa</region></placeName><orgName type="university">Université d'Helsinki</orgName></affiliation></author><author><name sortKey="Vikkula, M" sort="Vikkula, M" uniqKey="Vikkula M" first="M" last="Vikkula">M. 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type="istex">0C6224FE09B6014A9EA87B7DD432CAC3292ECC68</idno><idno type="DOI">10.1136/jmg.2008.064469</idno><idno type="href">jmedgenet-46-399.pdf</idno><idno type="ArticleID">mg64469</idno><idno type="PMID">19289394</idno><idno type="local">jmedgenet;46/6/399</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0022-2593</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Amino Acid Sequence</term><term>Amino Acid Substitution</term><term>Cell Line</term><term>Congenital</term><term>Genes, Recessive</term><term>Genetic disease</term><term>Genetics</term><term>Human</term><term>Humans</term><term>Lymphedema</term><term>Lymphedema (congenital)</term><term>Lymphedema (genetics)</term><term>Microscopy, Fluorescence</term><term>Molecular Sequence Data</term><term>Mutation</term><term>Pedigree</term><term>Recessive character</term><term>Sequence Alignment</term><term>Signal Transduction</term><term>Vascular Endothelial Growth Factor Receptor-3 (chemistry)</term><term>Vascular Endothelial Growth Factor Receptor-3 (genetics)</term><term>Vascular Endothelial Growth Factor Receptor-3 (metabolism)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Alignement de séquences</term><term>Données de séquences moléculaires</term><term>Gènes récessifs</term><term>Humains</term><term>Lignée cellulaire</term><term>Lymphoedème ()</term><term>Lymphoedème (génétique)</term><term>Microscopie de fluorescence</term><term>Mutation</term><term>Pedigree</term><term>Récepteur-3 au facteur croissance endothéliale vasculaire ()</term><term>Récepteur-3 au facteur croissance endothéliale vasculaire (génétique)</term><term>Récepteur-3 au facteur croissance endothéliale vasculaire (métabolisme)</term><term>Substitution d'acide aminé</term><term>Séquence d'acides aminés</term><term>Transduction du signal</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Vascular Endothelial Growth Factor Receptor-3</term></keywords><keywords scheme="MESH" qualifier="congenital" xml:lang="en"><term>Lymphedema</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Lymphedema</term><term>Vascular Endothelial Growth Factor Receptor-3</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Lymphoedème</term><term>Récepteur-3 au facteur croissance endothéliale vasculaire</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Vascular Endothelial Growth Factor Receptor-3</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Récepteur-3 au facteur croissance endothéliale vasculaire</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Amino Acid Sequence</term><term>Amino Acid Substitution</term><term>Cell Line</term><term>Genes, Recessive</term><term>Humans</term><term>Microscopy, Fluorescence</term><term>Molecular Sequence Data</term><term>Mutation</term><term>Pedigree</term><term>Sequence Alignment</term><term>Signal Transduction</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Alignement de séquences</term><term>Données de séquences moléculaires</term><term>Gènes récessifs</term><term>Humains</term><term>Lignée cellulaire</term><term>Lymphoedème</term><term>Microscopie de fluorescence</term><term>Mutation</term><term>Pedigree</term><term>Récepteur-3 au facteur croissance endothéliale vasculaire</term><term>Substitution d'acide aminé</term><term>Séquence d'acides aminés</term><term>Transduction du signal</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Caractère récessif</term><term>Congénital</term><term>Génétique</term><term>Homme</term><term>Lymphoedème</term><term>Maladie héréditaire</term><term>Mutation</term></keywords><keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Génétique</term><term>Homme</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract">Background: Heterozygous mutations in VEGFR3 have been identified in some familial cases with dominantly inherited primary congenital lymphoedema, known as Nonne–Milroy disease. Recessive cases of primary lymphoedema with a genetic cause are not known, except for two families with syndromic hypotrichosis–lymphoedema–telangiectasia, with a SOX18 mutation. Methods and results: In this study, we present the first case of isolated primary congenital lymphoedema with recessive inheritance, caused by a homozygous mutation in VEGFR3. The novel mutation is a transition from alanine-to-threonine in amino acid 855, located in the ATP binding domain of the VEGFR3 receptor. Assessment of receptor function showed impaired ligand induced internalisation and ERK1/2 activity. Moreover, receptor phosphorylation was reduced, although less so than for a kinase-dead VEGFR3 mutation, which causes Nonne–Milroy disease. Conclusion: A hypomorphic VEGFR3 mutation, with moderate effect on receptor function, in a homozygous state can result in insufficient lymphatic functioning. Thus, in addition to Nonne–Milroy disease with dominant inheritance, VEGFR3 alterations can cause isolated recessive primary congenital lymphoedema. These data expand our understanding of the aetiology of congenital lymphoedema and suggest that large scale screening of VEGFR3 in all primary lymphoedema patients is necessary.</div></front></TEI><affiliations><list><country><li>Belgique</li><li>Finlande</li><li>États-Unis</li></country><region><li>Massachusetts</li><li>Région de Bruxelles-Capitale</li><li>Uusimaa</li></region><settlement><li>Bruxelles</li><li>Helsinki</li><li>Louvain-la-Neuve</li></settlement><orgName><li>Université catholique de Louvain</li><li>Université d'Helsinki</li></orgName></list><tree><country name="Belgique"><region name="Région de Bruxelles-Capitale"><name sortKey="Ghalamkarpour, A" sort="Ghalamkarpour, A" uniqKey="Ghalamkarpour A" first="A" last="Ghalamkarpour">A. Ghalamkarpour</name></region><name sortKey="Boon, L M" sort="Boon, L M" uniqKey="Boon L" first="L M" last="Boon">L M Boon</name><name sortKey="Boon, L M" sort="Boon, L M" uniqKey="Boon L" first="L M" last="Boon">L M Boon</name><name sortKey="Vikkula, M" sort="Vikkula, M" uniqKey="Vikkula M" first="M" last="Vikkula">M. Vikkula</name></country><country name="Finlande"><noRegion><name sortKey="Holnthoner, W" sort="Holnthoner, W" uniqKey="Holnthoner W" first="W" last="Holnthoner">W. Holnthoner</name></noRegion><name sortKey="Alitalo, K" sort="Alitalo, K" uniqKey="Alitalo K" first="K" last="Alitalo">Kari Alitalo</name><name sortKey="Saharinen, P" sort="Saharinen, P" uniqKey="Saharinen P" first="P" last="Saharinen">P. Saharinen</name></country><country name="États-Unis"><region name="Massachusetts"><name sortKey="Mulliken, J B" sort="Mulliken, J B" uniqKey="Mulliken J" first="J B" last="Mulliken">J B Mulliken</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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