LymphedemaV1, PubMed, Checkpoint, bibRecord, 003759

The establishment of a predictive mutational model of the forkhead domain through the analyses of FOXC2 missense mutations identified in patients with hereditary lymphedema with distichiasis.

Identifieur interne : 003759 ( PubMed/Checkpoint ); précédent : 003758; suivant : 003760

The establishment of a predictive mutational model of the forkhead domain through the analyses of FOXC2 missense mutations identified in patients with hereditary lymphedema with distichiasis.

Auteurs : Fred B. Berry [Canada] ; Yahya Tamimi ; Michelle V. Carle ; Ordan J. Lehmann ; Michael A. Walter

Source :

Human molecular genetics [ 0964-6906 ] ; 2005.

RBID : pubmed:16081467

Descripteurs français

English descriptors

KwdEn :
- Amino Acid Sequence, DNA Primers, Electrophoretic Mobility Shift Assay, Eyelashes (abnormalities), Fluorescent Antibody Technique, Forkhead Transcription Factors (genetics), Humans, Luciferases, Lymphedema (complications), Lymphedema (genetics), Models, Genetic, Models, Molecular, Molecular Sequence Data, Mutagenesis, Site-Directed, Mutation, Missense (genetics), Sequence Analysis, DNA.
MESH :
- chemical , genetics : Forkhead Transcription Factors.
- chemical : DNA Primers, Luciferases.
- abnormalities : Eyelashes.
- complications : Lymphedema.
- genetics : Lymphedema, Mutation, Missense.
- Amino Acid Sequence, Electrophoretic Mobility Shift Assay, Fluorescent Antibody Technique, Humans, Models, Genetic, Models, Molecular, Molecular Sequence Data, Mutagenesis, Site-Directed, Sequence Analysis, DNA.

Abstract

The FOX family of transcription factor genes is an evolutionary conserved, yet functionally diverse class of transcription factors that are important for regulation of energy homeostasis, development and oncogenesis. The proteins encoded by FOX genes are characterized by a conserved DNA-binding domain known as the forkhead domain (FHD). To date, disease-causing mutations have been identified in eight human FOX genes. Many of these mutations result in single amino acid substitutions in the FHD. We analyzed the molecular consequences of two disease-causing missense mutations (R121H and S125L) occurring in the FHD of the FOXC2 gene that were identified in patients with hereditary lymphedema with distichiasis (LD) to test the predictive capacity of a FHD structure/function model. On the basis of the FOXC2 solution structure, both FOXC2 missense mutations are located on the DNA-recognition helix of the FHD. A mutation model based on the parologous FOXC1 protein predicts that these FOXC2 missense mutations will impair the DNA-binding and transcriptional activation ability of the FOXC2 protein. When these mutations were analyzed biochemically, we found that both mutations did indeed reduce the DNA binding and transcriptional capacity. In addition, the R121H mutation affected nuclear localization of FOXC2. Together, these data indicate that these FOXC2 missense mutations are functional nulls and that FOXC2 haploinsufficiency underlies hereditary LD and validates the predictive ability of the FOXC1-based FHD mutational model.

DOI: 10.1093/hmg/ddi295
PubMed: 16081467

Affiliations:

Canada

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Le document en format XML

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<affiliation wicri:level="1"><nlm:affiliation>Department of Ophthalmology, University of Alberta, Edmonton, Alberta, Canada T6G 2H7. fberry@ualberta.ca</nlm:affiliation>
<country>Canada</country>
<wicri:regionArea>Department of Ophthalmology, University of Alberta, Edmonton, Alberta</wicri:regionArea>
<wicri:noRegion>Alberta</wicri:noRegion>
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<author><name sortKey="Tamimi, Yahya" sort="Tamimi, Yahya" uniqKey="Tamimi Y" first="Yahya" last="Tamimi">Yahya Tamimi</name>
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<author><name sortKey="Carle, Michelle V" sort="Carle, Michelle V" uniqKey="Carle M" first="Michelle V" last="Carle">Michelle V. Carle</name>
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<author><name sortKey="Lehmann, Ordan J" sort="Lehmann, Ordan J" uniqKey="Lehmann O" first="Ordan J" last="Lehmann">Ordan J. Lehmann</name>
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<author><name sortKey="Walter, Michael A" sort="Walter, Michael A" uniqKey="Walter M" first="Michael A" last="Walter">Michael A. Walter</name>
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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Amino Acid Sequence</term>
<term>DNA Primers</term>
<term>Electrophoretic Mobility Shift Assay</term>
<term>Eyelashes (abnormalities)</term>
<term>Fluorescent Antibody Technique</term>
<term>Forkhead Transcription Factors (genetics)</term>
<term>Humans</term>
<term>Luciferases</term>
<term>Lymphedema (complications)</term>
<term>Lymphedema (genetics)</term>
<term>Models, Genetic</term>
<term>Models, Molecular</term>
<term>Molecular Sequence Data</term>
<term>Mutagenesis, Site-Directed</term>
<term>Mutation, Missense (genetics)</term>
<term>Sequence Analysis, DNA</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Amorces ADN</term>
<term>Analyse de séquence d'ADN</term>
<term>Cils (malformations)</term>
<term>Données de séquences moléculaires</term>
<term>Facteurs de transcription Forkhead (génétique)</term>
<term>Humains</term>
<term>Luciferases</term>
<term>Lymphoedème ()</term>
<term>Lymphoedème (génétique)</term>
<term>Modèles génétiques</term>
<term>Modèles moléculaires</term>
<term>Mutagenèse dirigée</term>
<term>Mutation faux-sens (génétique)</term>
<term>Séquence d'acides aminés</term>
<term>Technique d'immunofluorescence</term>
<term>Test de retard de migration électrophorétique</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Forkhead Transcription Factors</term>
</keywords>
<keywords scheme="MESH" type="chemical" xml:lang="en"><term>DNA Primers</term>
<term>Luciferases</term>
</keywords>
<keywords scheme="MESH" qualifier="abnormalities" xml:lang="en"><term>Eyelashes</term>
</keywords>
<keywords scheme="MESH" qualifier="complications" xml:lang="en"><term>Lymphedema</term>
</keywords>
<keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Lymphedema</term>
<term>Mutation, Missense</term>
</keywords>
<keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Facteurs de transcription Forkhead</term>
<term>Lymphoedème</term>
<term>Mutation faux-sens</term>
</keywords>
<keywords scheme="MESH" qualifier="malformations" xml:lang="fr"><term>Cils</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Amino Acid Sequence</term>
<term>Electrophoretic Mobility Shift Assay</term>
<term>Fluorescent Antibody Technique</term>
<term>Humans</term>
<term>Models, Genetic</term>
<term>Models, Molecular</term>
<term>Molecular Sequence Data</term>
<term>Mutagenesis, Site-Directed</term>
<term>Sequence Analysis, DNA</term>
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<keywords scheme="MESH" xml:lang="fr"><term>Amorces ADN</term>
<term>Analyse de séquence d'ADN</term>
<term>Données de séquences moléculaires</term>
<term>Humains</term>
<term>Luciferases</term>
<term>Lymphoedème</term>
<term>Modèles génétiques</term>
<term>Modèles moléculaires</term>
<term>Mutagenèse dirigée</term>
<term>Séquence d'acides aminés</term>
<term>Technique d'immunofluorescence</term>
<term>Test de retard de migration électrophorétique</term>
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<front><div type="abstract" xml:lang="en">The FOX family of transcription factor genes is an evolutionary conserved, yet functionally diverse class of transcription factors that are important for regulation of energy homeostasis, development and oncogenesis. The proteins encoded by FOX genes are characterized by a conserved DNA-binding domain known as the forkhead domain (FHD). To date, disease-causing mutations have been identified in eight human FOX genes. Many of these mutations result in single amino acid substitutions in the FHD. We analyzed the molecular consequences of two disease-causing missense mutations (R121H and S125L) occurring in the FHD of the FOXC2 gene that were identified in patients with hereditary lymphedema with distichiasis (LD) to test the predictive capacity of a FHD structure/function model. On the basis of the FOXC2 solution structure, both FOXC2 missense mutations are located on the DNA-recognition helix of the FHD. A mutation model based on the parologous FOXC1 protein predicts that these FOXC2 missense mutations will impair the DNA-binding and transcriptional activation ability of the FOXC2 protein. When these mutations were analyzed biochemically, we found that both mutations did indeed reduce the DNA binding and transcriptional capacity. In addition, the R121H mutation affected nuclear localization of FOXC2. Together, these data indicate that these FOXC2 missense mutations are functional nulls and that FOXC2 haploinsufficiency underlies hereditary LD and validates the predictive ability of the FOXC1-based FHD mutational model.</div>
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<Abstract><AbstractText>The FOX family of transcription factor genes is an evolutionary conserved, yet functionally diverse class of transcription factors that are important for regulation of energy homeostasis, development and oncogenesis. The proteins encoded by FOX genes are characterized by a conserved DNA-binding domain known as the forkhead domain (FHD). To date, disease-causing mutations have been identified in eight human FOX genes. Many of these mutations result in single amino acid substitutions in the FHD. We analyzed the molecular consequences of two disease-causing missense mutations (R121H and S125L) occurring in the FHD of the FOXC2 gene that were identified in patients with hereditary lymphedema with distichiasis (LD) to test the predictive capacity of a FHD structure/function model. On the basis of the FOXC2 solution structure, both FOXC2 missense mutations are located on the DNA-recognition helix of the FHD. A mutation model based on the parologous FOXC1 protein predicts that these FOXC2 missense mutations will impair the DNA-binding and transcriptional activation ability of the FOXC2 protein. When these mutations were analyzed biochemically, we found that both mutations did indeed reduce the DNA binding and transcriptional capacity. In addition, the R121H mutation affected nuclear localization of FOXC2. Together, these data indicate that these FOXC2 missense mutations are functional nulls and that FOXC2 haploinsufficiency underlies hereditary LD and validates the predictive ability of the FOXC1-based FHD mutational model.</AbstractText>
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The establishment of a predictive mutational model of the forkhead domain through the analyses of FOXC2 missense mutations identified in patients with hereditary lymphedema with distichiasis.

The establishment of a predictive mutational model of the forkhead domain through the analyses of FOXC2 missense mutations identified in patients with hereditary lymphedema with distichiasis.

Source :

Descripteurs français

English descriptors

Abstract

Links toward previous steps (curation, corpus...)

Links to Exploration step

Le document en format XML

Pour manipuler ce document sous Unix (Dilib)

Pour mettre un lien sur cette page dans le réseau Wicri

Pour générer des pages wiki