Novel missense mutations in the FOXC2 gene alter transcriptional activity.
Identifieur interne : 003620 ( Ncbi/Checkpoint ); précédent : 003619; suivant : 003621Novel missense mutations in the FOXC2 gene alter transcriptional activity.
Auteurs : M A M. Van Steensel [Pays-Bas] ; R J Damstra ; M V Heitink ; R S Bladergroen ; J. Veraart ; Peter M. Steijlen ; M. Van GeelSource :
- Human mutation [ 1098-1004 ] ; 2009.
Descripteurs français
- KwdFr :
- Activation de la transcription (génétique), Animaux, Cellules COS, Cellules HeLa, Cercopithecus aethiops, Facteurs de transcription Forkhead (génétique), Humains, Lymphoedème (génétique), Lymphoedème (imagerie diagnostique), Mutation faux-sens (génétique), Noyau de la cellule (métabolisme), Phénotype, Protéines mutantes (génétique), Protéines mutantes (métabolisme), Scintigraphie, Souris, Transcription génétique, Transport de protéines.
- MESH :
- génétique : Activation de la transcription, Facteurs de transcription Forkhead, Lymphoedème, Mutation faux-sens, Protéines mutantes.
- imagerie diagnostique : Lymphoedème.
- métabolisme : Noyau de la cellule, Protéines mutantes.
- Animaux, Cellules COS, Cellules HeLa, Cercopithecus aethiops, Humains, Phénotype, Scintigraphie, Souris, Transcription génétique, Transport de protéines.
English descriptors
- KwdEn :
- Animals, COS Cells, Cell Nucleus (metabolism), Cercopithecus aethiops, Forkhead Transcription Factors (genetics), HeLa Cells, Humans, Lymphedema (diagnostic imaging), Lymphedema (genetics), Mice, Mutant Proteins (genetics), Mutant Proteins (metabolism), Mutation, Missense (genetics), Phenotype, Protein Transport, Radionuclide Imaging, Transcription, Genetic, Transcriptional Activation (genetics).
- MESH :
- chemical , genetics : Forkhead Transcription Factors, Mutant Proteins.
- diagnostic imaging : Lymphedema.
- genetics : Lymphedema, Mutation, Missense, Transcriptional Activation.
- metabolism : Cell Nucleus, Mutant Proteins.
- Animals, COS Cells, Cercopithecus aethiops, HeLa Cells, Humans, Mice, Phenotype, Protein Transport, Radionuclide Imaging, Transcription, Genetic.
Abstract
Mutations in the FOXC2 gene that codes for a forkhead transcription factor are associated with primary lymphedema that usually develops around puberty. Associated abnormalities include distichiasis and, very frequently, superficial and deep venous insufficiency. Most mutations reported so far either truncate the protein or are missense mutations in the forkhead domain causing a loss of function. The haplo-insufficient state is associated with lymphatic hyperplasia in mice as well as in humans. We analyzed the FOXC2 gene in 288 patients with primary lymphedema and found 11 pathogenic mutations, of which 9 are novel. Of those, 5 were novel missense mutations of which 4 were located outside of the forkhead domain. To examine their pathogenic potential we performed a transactivation assay using a luciferase reporter construct driven by FOXC1 response elements. We found that the mutations outside the forkhead domain cause a gain of function as measured by luciferase activity. Patient characteristics conform to previous reports with the exception of distichiasis, which was found in only 2 patients out of 11. FOXC2 mutations causing lymphedema-distichiasis syndrome reported thus far result in haplo-insufficiency and lead to lymphatic hyperplasia. Our results suggest that gain-of-function mutations may also cause lymphedema. One would expect that in this case, lymphatic hypoplasia would be the underlying abnormality. Patients with activating mutations might present with Meige disease.
DOI: 10.1002/humu.21127
PubMed: 19760751
Affiliations:
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Van Steensel</name><affiliation wicri:level="1"><nlm:affiliation>Departments of dermatology, Maastricht University Medical Center, Maastricht, the Netherlands. m.van.steensel@mumc.nl</nlm:affiliation><country xml:lang="fr" wicri:curation="lc">Pays-Bas</country><wicri:regionArea>Departments of dermatology, Maastricht University Medical Center, Maastricht</wicri:regionArea><wicri:noRegion>Maastricht</wicri:noRegion></affiliation></author><author><name sortKey="Damstra, R J" sort="Damstra, R J" uniqKey="Damstra R" first="R J" last="Damstra">R J Damstra</name></author><author><name sortKey="Heitink, M V" sort="Heitink, M V" uniqKey="Heitink M" first="M V" last="Heitink">M V Heitink</name></author><author><name sortKey="Bladergroen, R S" sort="Bladergroen, R S" uniqKey="Bladergroen R" first="R S" last="Bladergroen">R S Bladergroen</name></author><author><name sortKey="Veraart, J" sort="Veraart, J" uniqKey="Veraart J" first="J" last="Veraart">J. Veraart</name></author><author><name sortKey="Steijlen, Peter M" sort="Steijlen, Peter M" uniqKey="Steijlen P" first="Peter M" last="Steijlen">Peter M. Steijlen</name></author><author><name sortKey="Van Geel, M" sort="Van Geel, M" uniqKey="Van Geel M" first="M" last="Van Geel">M. 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Van Steensel</name><affiliation wicri:level="1"><nlm:affiliation>Departments of dermatology, Maastricht University Medical Center, Maastricht, the Netherlands. m.van.steensel@mumc.nl</nlm:affiliation><country xml:lang="fr" wicri:curation="lc">Pays-Bas</country><wicri:regionArea>Departments of dermatology, Maastricht University Medical Center, Maastricht</wicri:regionArea><wicri:noRegion>Maastricht</wicri:noRegion></affiliation></author><author><name sortKey="Damstra, R J" sort="Damstra, R J" uniqKey="Damstra R" first="R J" last="Damstra">R J Damstra</name></author><author><name sortKey="Heitink, M V" sort="Heitink, M V" uniqKey="Heitink M" first="M V" last="Heitink">M V Heitink</name></author><author><name sortKey="Bladergroen, R S" sort="Bladergroen, R S" uniqKey="Bladergroen R" first="R S" last="Bladergroen">R S Bladergroen</name></author><author><name sortKey="Veraart, J" sort="Veraart, J" uniqKey="Veraart J" first="J" last="Veraart">J. Veraart</name></author><author><name sortKey="Steijlen, Peter M" sort="Steijlen, Peter M" uniqKey="Steijlen P" first="Peter M" last="Steijlen">Peter M. Steijlen</name></author><author><name sortKey="Van Geel, M" sort="Van Geel, M" uniqKey="Van Geel M" first="M" last="Van Geel">M. Van Geel</name></author></analytic><series><title level="j">Human mutation</title><idno type="eISSN">1098-1004</idno><imprint><date when="2009" type="published">2009</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>COS Cells</term><term>Cell Nucleus (metabolism)</term><term>Cercopithecus aethiops</term><term>Forkhead Transcription Factors (genetics)</term><term>HeLa Cells</term><term>Humans</term><term>Lymphedema (diagnostic imaging)</term><term>Lymphedema (genetics)</term><term>Mice</term><term>Mutant Proteins (genetics)</term><term>Mutant Proteins (metabolism)</term><term>Mutation, Missense (genetics)</term><term>Phenotype</term><term>Protein Transport</term><term>Radionuclide Imaging</term><term>Transcription, Genetic</term><term>Transcriptional Activation (genetics)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Activation de la transcription (génétique)</term><term>Animaux</term><term>Cellules COS</term><term>Cellules HeLa</term><term>Cercopithecus aethiops</term><term>Facteurs de transcription Forkhead (génétique)</term><term>Humains</term><term>Lymphoedème (génétique)</term><term>Lymphoedème (imagerie diagnostique)</term><term>Mutation faux-sens (génétique)</term><term>Noyau de la cellule (métabolisme)</term><term>Phénotype</term><term>Protéines mutantes (génétique)</term><term>Protéines mutantes (métabolisme)</term><term>Scintigraphie</term><term>Souris</term><term>Transcription génétique</term><term>Transport de protéines</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Forkhead Transcription Factors</term><term>Mutant Proteins</term></keywords><keywords scheme="MESH" qualifier="diagnostic imaging" xml:lang="en"><term>Lymphedema</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Lymphedema</term><term>Mutation, Missense</term><term>Transcriptional Activation</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Activation de la transcription</term><term>Facteurs de transcription Forkhead</term><term>Lymphoedème</term><term>Mutation faux-sens</term><term>Protéines mutantes</term></keywords><keywords scheme="MESH" qualifier="imagerie diagnostique" xml:lang="fr"><term>Lymphoedème</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Cell Nucleus</term><term>Mutant Proteins</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Noyau de la cellule</term><term>Protéines mutantes</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>COS Cells</term><term>Cercopithecus aethiops</term><term>HeLa Cells</term><term>Humans</term><term>Mice</term><term>Phenotype</term><term>Protein Transport</term><term>Radionuclide Imaging</term><term>Transcription, Genetic</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Cellules COS</term><term>Cellules HeLa</term><term>Cercopithecus aethiops</term><term>Humains</term><term>Phénotype</term><term>Scintigraphie</term><term>Souris</term><term>Transcription génétique</term><term>Transport de protéines</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Mutations in the FOXC2 gene that codes for a forkhead transcription factor are associated with primary lymphedema that usually develops around puberty. Associated abnormalities include distichiasis and, very frequently, superficial and deep venous insufficiency. Most mutations reported so far either truncate the protein or are missense mutations in the forkhead domain causing a loss of function. The haplo-insufficient state is associated with lymphatic hyperplasia in mice as well as in humans. We analyzed the FOXC2 gene in 288 patients with primary lymphedema and found 11 pathogenic mutations, of which 9 are novel. Of those, 5 were novel missense mutations of which 4 were located outside of the forkhead domain. To examine their pathogenic potential we performed a transactivation assay using a luciferase reporter construct driven by FOXC1 response elements. We found that the mutations outside the forkhead domain cause a gain of function as measured by luciferase activity. Patient characteristics conform to previous reports with the exception of distichiasis, which was found in only 2 patients out of 11. FOXC2 mutations causing lymphedema-distichiasis syndrome reported thus far result in haplo-insufficiency and lead to lymphatic hyperplasia. Our results suggest that gain-of-function mutations may also cause lymphedema. One would expect that in this case, lymphatic hypoplasia would be the underlying abnormality. Patients with activating mutations might present with Meige disease.</div></front></TEI><affiliations><list><country><li>Pays-Bas</li></country></list><tree><noCountry><name sortKey="Bladergroen, R S" sort="Bladergroen, R S" uniqKey="Bladergroen R" first="R S" last="Bladergroen">R S Bladergroen</name><name sortKey="Damstra, R J" sort="Damstra, R J" uniqKey="Damstra R" first="R J" last="Damstra">R J Damstra</name><name sortKey="Heitink, M V" sort="Heitink, M V" uniqKey="Heitink M" first="M V" last="Heitink">M V Heitink</name><name sortKey="Steijlen, Peter M" sort="Steijlen, Peter M" uniqKey="Steijlen P" first="Peter M" last="Steijlen">Peter M. Steijlen</name><name sortKey="Van Geel, M" sort="Van Geel, M" uniqKey="Van Geel M" first="M" last="Van Geel">M. Van Geel</name><name sortKey="Veraart, J" sort="Veraart, J" uniqKey="Veraart J" first="J" last="Veraart">J. Veraart</name></noCountry><country name="Pays-Bas"><noRegion><name sortKey="Van Steensel, M A M" sort="Van Steensel, M A M" uniqKey="Van Steensel M" first="M A M" last="Van Steensel">M A M. Van Steensel</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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