LymphedemaV1, Ncbi, Merge, bibRecord, 007C46

A Multiplex Kindred with Hennekam Syndrome due to Homozygosity for a CCBE1 Mutation that does not Prevent Protein Expression

Identifieur interne : 007C46 ( Ncbi/Merge ); précédent : 007C45; suivant : 007C47

A Multiplex Kindred with Hennekam Syndrome due to Homozygosity for a CCBE1 Mutation that does not Prevent Protein Expression

Auteurs : Carolyn C. Jackson [États-Unis] ; Lucy Best [États-Unis] ; Lazaro Lorenzo [France] ; Jean-Laurent Casanova [États-Unis, France] ; Jochen Wacker [Allemagne] ; Simone Bertz [Allemagne] ; Abbas Agaimy [Allemagne] ; Thomas Harrer [Allemagne]

Source :

Journal of clinical immunology [ 0271-9142 ] ; 2015.

RBID : PMC:4984268

Descripteurs français

English descriptors

KwdEn :
- Adult, Calcium-Binding Proteins (genetics), Calcium-Binding Proteins (metabolism), Consanguinity, Craniofacial Abnormalities (diagnosis), Craniofacial Abnormalities (genetics), DNA Mutational Analysis, Female, Gene Expression Regulation (genetics), Homozygote, Humans, Lymphangiectasis, Intestinal (diagnosis), Lymphangiectasis, Intestinal (genetics), Lymphedema (diagnosis), Lymphedema (genetics), Male, Mutation (genetics), Pedigree, Siblings, Tumor Suppressor Proteins (genetics), Tumor Suppressor Proteins (metabolism), Turkey, Young Adult.
MESH :
- chemical , genetics : Calcium-Binding Proteins, Tumor Suppressor Proteins.
- chemical , metabolism : Calcium-Binding Proteins, Tumor Suppressor Proteins.
- diagnosis : Craniofacial Abnormalities, Lymphangiectasis, Intestinal, Lymphedema.
- genetics : Craniofacial Abnormalities, Gene Expression Regulation, Lymphangiectasis, Intestinal, Lymphedema, Mutation.
- Adult, Consanguinity, DNA Mutational Analysis, Female, Homozygote, Humans, Male, Pedigree, Siblings, Turkey, Young Adult.

Abstract

Collagen and calcium-binding EGF domain-containing protein 1 (CCBE1) bi-allelic mutations have been associated with syndromes of widespread congenital lymphatic dysplasia, including Hennekam Syndrome (HS). HS is characterized by lymphedema, lymphangiectasia, and intellectual disability. CCBE1 encodes a putative extracellular matrix protein but the HS-causing mutations have not been studied biochemically. We report two HS siblings, born to consanguineous parents of Turkish ancestry, whose clinical phenotype also includes protein losing enteropathy, painful relapsing chylous ascites, and hypogammaglobulinemia. We identified by whole exome and Sanger sequencing the homozygous CCBE1 C174Y mutation in both siblings. This mutation had been previously reported in another HS kindred from the Netherlands. In over-expression studies, we found increased intracellular expression of all forms (monomers, dimers, trimers) of the CCBE1 C174Y mutant protein, by Western blot, despite mutant mRNA levels similar to wild-type (WT). In addition, we detected increased secretion of the mutant CCBE1 protein by ELISA. We further found the mutant and WT proteins to be evenly distributed in the cytoplasm, by immunofluorescence and confocal microscopy. Finally, we found a strong decrease of lymphatic vessels, with a corresponding diminished expression of CCBE1, by immunohistochemistry of the patients’ intestinal biopsies. In contrast, mucosal blood vessels and muscularis mucosae showed normal CCBE1 staining. Our findings show that the mutant CCBE1 C174Y protein is not loss-of-function by loss-of-expression.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4984268

DOI: 10.1007/s10875-015-0225-6
PubMed: 26686525
PubMed Central: 4984268

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PMC:4984268

Le document en format XML

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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">A Multiplex Kindred with Hennekam Syndrome due to Homozygosity for a <italic>CCBE1</italic>
 Mutation that does not Prevent Protein Expression</title>
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<term>Analyse de mutations d'ADN</term>
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<term>Homozygote</term>
<term>Humains</term>
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<term>Lymphangiectasie intestinale (génétique)</term>
<term>Lymphoedème (diagnostic)</term>
<term>Lymphoedème (génétique)</term>
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<term>Pedigree</term>
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<term>Protéines suppresseurs de tumeurs (métabolisme)</term>
<term>Régulation de l'expression des gènes (génétique)</term>
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<term>Mutation</term>
</keywords>
<keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Lymphangiectasie intestinale</term>
<term>Lymphoedème</term>
<term>Malformations crâniofaciales</term>
<term>Mutation</term>
<term>Protéines de liaison au calcium</term>
<term>Protéines suppresseurs de tumeurs</term>
<term>Régulation de l'expression des gènes</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Protéines de liaison au calcium</term>
<term>Protéines suppresseurs de tumeurs</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Adult</term>
<term>Consanguinity</term>
<term>DNA Mutational Analysis</term>
<term>Female</term>
<term>Homozygote</term>
<term>Humans</term>
<term>Male</term>
<term>Pedigree</term>
<term>Siblings</term>
<term>Turkey</term>
<term>Young Adult</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Adulte</term>
<term>Analyse de mutations d'ADN</term>
<term>Consanguinité</term>
<term>Femelle</term>
<term>Fratrie</term>
<term>Homozygote</term>
<term>Humains</term>
<term>Jeune adulte</term>
<term>Mâle</term>
<term>Pedigree</term>
<term>Turquie</term>
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<front><div type="abstract" xml:lang="en"><p id="P1">Collagen and calcium-binding EGF domain-containing protein 1 (<italic>CCBE1</italic>
) bi-allelic mutations have been associated with syndromes of widespread congenital lymphatic dysplasia, including Hennekam Syndrome (HS). HS is characterized by lymphedema, lymphangiectasia, and intellectual disability. <italic>CCBE1</italic>
 encodes a putative extracellular matrix protein but the HS-causing mutations have not been studied biochemically. We report two HS siblings, born to consanguineous parents of Turkish ancestry, whose clinical phenotype also includes protein losing enteropathy, painful relapsing chylous ascites, and hypogammaglobulinemia. We identified by whole exome and Sanger sequencing the homozygous CCBE1 C174Y mutation in both siblings. This mutation had been previously reported in another HS kindred from the Netherlands. In over-expression studies, we found increased intracellular expression of all forms (monomers, dimers, trimers) of the CCBE1 C174Y mutant protein, by Western blot, despite mutant mRNA levels similar to wild-type (WT). In addition, we detected increased secretion of the mutant CCBE1 protein by ELISA. We further found the mutant and WT proteins to be evenly distributed in the cytoplasm, by immunofluorescence and confocal microscopy. Finally, we found a strong decrease of lymphatic vessels, with a corresponding diminished expression of CCBE1, by immunohistochemistry of the patients’ intestinal biopsies. In contrast, mucosal blood vessels and muscularis mucosae showed normal CCBE1 staining. Our findings show that the mutant CCBE1 C174Y protein is not loss-of-function by loss-of-expression.</p>
</div>
</front>
</TEI>
<double pmid="26686525"><pmc><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">A Multiplex Kindred with Hennekam Syndrome due to Homozygosity for a <italic>CCBE1</italic>
 Mutation that does not Prevent Protein Expression</title>
<author><name sortKey="Jackson, Carolyn C" sort="Jackson, Carolyn C" uniqKey="Jackson C" first="Carolyn C." last="Jackson">Carolyn C. Jackson</name>
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<wicri:noRegion>NY</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Best, Lucy" sort="Best, Lucy" uniqKey="Best L" first="Lucy" last="Best">Lucy Best</name>
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</affiliation>
</author>
<author><name sortKey="Lorenzo, Lazaro" sort="Lorenzo, Lazaro" uniqKey="Lorenzo L" first="Lazaro" last="Lorenzo">Lazaro Lorenzo</name>
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<country xml:lang="fr">France</country>
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<region type="old region">Île-de-France</region>
<settlement type="city">Paris</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Casanova, Jean Laurent" sort="Casanova, Jean Laurent" uniqKey="Casanova J" first="Jean-Laurent" last="Casanova">Jean-Laurent Casanova</name>
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<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY</wicri:regionArea>
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<region type="old region">Île-de-France</region>
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</placeName>
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<author><name sortKey="Wacker, Jochen" sort="Wacker, Jochen" uniqKey="Wacker J" first="Jochen" last="Wacker">Jochen Wacker</name>
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<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Department of Pathology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen</wicri:regionArea>
<placeName><settlement type="city">Erlangen</settlement>
<region type="land" nuts="1">Bavière</region>
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</author>
<author><name sortKey="Bertz, Simone" sort="Bertz, Simone" uniqKey="Bertz S" first="Simone" last="Bertz">Simone Bertz</name>
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<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Department of Pathology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen</wicri:regionArea>
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<region type="land" nuts="1">Bavière</region>
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<author><name sortKey="Agaimy, Abbas" sort="Agaimy, Abbas" uniqKey="Agaimy A" first="Abbas" last="Agaimy">Abbas Agaimy</name>
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<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Department of Pathology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen</wicri:regionArea>
<placeName><settlement type="city">Erlangen</settlement>
<region type="land" nuts="1">Bavière</region>
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</placeName>
</affiliation>
</author>
<author><name sortKey="Harrer, Thomas" sort="Harrer, Thomas" uniqKey="Harrer T" first="Thomas" last="Harrer">Thomas Harrer</name>
<affiliation wicri:level="3"><nlm:aff id="A8">Department for Internal Medicine III, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Department for Internal Medicine III, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen</wicri:regionArea>
<placeName><settlement type="city">Erlangen</settlement>
<region type="land" nuts="1">Bavière</region>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">A Multiplex Kindred with Hennekam Syndrome due to Homozygosity for a <italic>CCBE1</italic>
 Mutation that does not Prevent Protein Expression</title>
<author><name sortKey="Jackson, Carolyn C" sort="Jackson, Carolyn C" uniqKey="Jackson C" first="Carolyn C." last="Jackson">Carolyn C. Jackson</name>
<affiliation wicri:level="1"><nlm:aff id="A1">St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY</wicri:regionArea>
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</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A2">Department of Pediatrics, The Memorial Sloan Kettering Cancer Center, New York, NY, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Pediatrics, The Memorial Sloan Kettering Cancer Center, New York, NY</wicri:regionArea>
<wicri:noRegion>NY</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Best, Lucy" sort="Best, Lucy" uniqKey="Best L" first="Lucy" last="Best">Lucy Best</name>
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<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY</wicri:regionArea>
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</affiliation>
</author>
<author><name sortKey="Lorenzo, Lazaro" sort="Lorenzo, Lazaro" uniqKey="Lorenzo L" first="Lazaro" last="Lorenzo">Lazaro Lorenzo</name>
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<country xml:lang="fr">France</country>
<wicri:regionArea>Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, INSERM, Paris</wicri:regionArea>
<placeName><region type="region">Île-de-France</region>
<region type="old region">Île-de-France</region>
<settlement type="city">Paris</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Casanova, Jean Laurent" sort="Casanova, Jean Laurent" uniqKey="Casanova J" first="Jean-Laurent" last="Casanova">Jean-Laurent Casanova</name>
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<country xml:lang="fr">États-Unis</country>
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<region type="old region">Île-de-France</region>
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</placeName>
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<affiliation wicri:level="1"><nlm:aff id="A4">Howard Hughes Medical Institute, New York, NY, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Howard Hughes Medical Institute, New York, NY</wicri:regionArea>
<wicri:noRegion>NY</wicri:noRegion>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="A5">Paris Descartes University, Imagine Institute, Paris, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Paris Descartes University, Imagine Institute, Paris</wicri:regionArea>
<placeName><region type="region">Île-de-France</region>
<region type="old region">Île-de-France</region>
<settlement type="city">Paris</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="A6">Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, Paris, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, Paris</wicri:regionArea>
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<region type="old region">Île-de-France</region>
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</placeName>
</affiliation>
</author>
<author><name sortKey="Wacker, Jochen" sort="Wacker, Jochen" uniqKey="Wacker J" first="Jochen" last="Wacker">Jochen Wacker</name>
<affiliation wicri:level="3"><nlm:aff id="A7">Department of Pathology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Department of Pathology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen</wicri:regionArea>
<placeName><settlement type="city">Erlangen</settlement>
<region type="land" nuts="1">Bavière</region>
<region type="district" nuts="2">District de Moyenne-Franconie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Bertz, Simone" sort="Bertz, Simone" uniqKey="Bertz S" first="Simone" last="Bertz">Simone Bertz</name>
<affiliation wicri:level="3"><nlm:aff id="A7">Department of Pathology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Department of Pathology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen</wicri:regionArea>
<placeName><settlement type="city">Erlangen</settlement>
<region type="land" nuts="1">Bavière</region>
<region type="district" nuts="2">District de Moyenne-Franconie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Agaimy, Abbas" sort="Agaimy, Abbas" uniqKey="Agaimy A" first="Abbas" last="Agaimy">Abbas Agaimy</name>
<affiliation wicri:level="3"><nlm:aff id="A7">Department of Pathology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Department of Pathology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen</wicri:regionArea>
<placeName><settlement type="city">Erlangen</settlement>
<region type="land" nuts="1">Bavière</region>
<region type="district" nuts="2">District de Moyenne-Franconie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Harrer, Thomas" sort="Harrer, Thomas" uniqKey="Harrer T" first="Thomas" last="Harrer">Thomas Harrer</name>
<affiliation wicri:level="3"><nlm:aff id="A8">Department for Internal Medicine III, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Department for Internal Medicine III, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen</wicri:regionArea>
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<region type="land" nuts="1">Bavière</region>
<region type="district" nuts="2">District de Moyenne-Franconie</region>
</placeName>
</affiliation>
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<series><title level="j">Journal of clinical immunology</title>
<idno type="ISSN">0271-9142</idno>
<idno type="eISSN">1573-2592</idno>
<imprint><date when="2015">2015</date>
</imprint>
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<front><div type="abstract" xml:lang="en"><p id="P1">Collagen and calcium-binding EGF domain-containing protein 1 (<italic>CCBE1</italic>
) bi-allelic mutations have been associated with syndromes of widespread congenital lymphatic dysplasia, including Hennekam Syndrome (HS). HS is characterized by lymphedema, lymphangiectasia, and intellectual disability. <italic>CCBE1</italic>
 encodes a putative extracellular matrix protein but the HS-causing mutations have not been studied biochemically. We report two HS siblings, born to consanguineous parents of Turkish ancestry, whose clinical phenotype also includes protein losing enteropathy, painful relapsing chylous ascites, and hypogammaglobulinemia. We identified by whole exome and Sanger sequencing the homozygous CCBE1 C174Y mutation in both siblings. This mutation had been previously reported in another HS kindred from the Netherlands. In over-expression studies, we found increased intracellular expression of all forms (monomers, dimers, trimers) of the CCBE1 C174Y mutant protein, by Western blot, despite mutant mRNA levels similar to wild-type (WT). In addition, we detected increased secretion of the mutant CCBE1 protein by ELISA. We further found the mutant and WT proteins to be evenly distributed in the cytoplasm, by immunofluorescence and confocal microscopy. Finally, we found a strong decrease of lymphatic vessels, with a corresponding diminished expression of CCBE1, by immunohistochemistry of the patients’ intestinal biopsies. In contrast, mucosal blood vessels and muscularis mucosae showed normal CCBE1 staining. Our findings show that the mutant CCBE1 C174Y protein is not loss-of-function by loss-of-expression.</p>
</div>
</front>
</TEI>
</pmc>
<pubmed><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">A Multiplex Kindred with Hennekam Syndrome due to Homozygosity for a CCBE1 Mutation that does not Prevent Protein Expression.</title>
<author><name sortKey="Jackson, Carolyn C" sort="Jackson, Carolyn C" uniqKey="Jackson C" first="Carolyn C" last="Jackson">Carolyn C. Jackson</name>
<affiliation wicri:level="2"><nlm:affiliation>St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA. cjackson@rockefeller.edu.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY</wicri:regionArea>
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</placeName>
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</author>
<author><name sortKey="Best, Lucy" sort="Best, Lucy" uniqKey="Best L" first="Lucy" last="Best">Lucy Best</name>
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<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Lorenzo, Lazaro" sort="Lorenzo, Lazaro" uniqKey="Lorenzo L" first="Lazaro" last="Lorenzo">Lazaro Lorenzo</name>
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<country xml:lang="fr">France</country>
<wicri:regionArea>Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, INSERM, Paris</wicri:regionArea>
<placeName><region type="region">Île-de-France</region>
<region type="old region">Île-de-France</region>
<settlement type="city">Paris</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Casanova, Jean Laurent" sort="Casanova, Jean Laurent" uniqKey="Casanova J" first="Jean-Laurent" last="Casanova">Jean-Laurent Casanova</name>
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<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY</wicri:regionArea>
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</affiliation>
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<author><name sortKey="Wacker, Jochen" sort="Wacker, Jochen" uniqKey="Wacker J" first="Jochen" last="Wacker">Jochen Wacker</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Pathology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.</nlm:affiliation>
<country xml:lang="fr">Allemagne</country>
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<author><name sortKey="Agaimy, Abbas" sort="Agaimy, Abbas" uniqKey="Agaimy A" first="Abbas" last="Agaimy">Abbas Agaimy</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Pathology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.</nlm:affiliation>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Department of Pathology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen</wicri:regionArea>
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<author><name sortKey="Harrer, Thomas" sort="Harrer, Thomas" uniqKey="Harrer T" first="Thomas" last="Harrer">Thomas Harrer</name>
<affiliation wicri:level="3"><nlm:affiliation>Department for Internal Medicine III, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.</nlm:affiliation>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Department for Internal Medicine III, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen</wicri:regionArea>
<placeName><settlement type="city">Erlangen</settlement>
<region type="land" nuts="1">Bavière</region>
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<sourceDesc><biblStruct><analytic><title xml:lang="en">A Multiplex Kindred with Hennekam Syndrome due to Homozygosity for a CCBE1 Mutation that does not Prevent Protein Expression.</title>
<author><name sortKey="Jackson, Carolyn C" sort="Jackson, Carolyn C" uniqKey="Jackson C" first="Carolyn C" last="Jackson">Carolyn C. Jackson</name>
<affiliation wicri:level="2"><nlm:affiliation>St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA. cjackson@rockefeller.edu.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Best, Lucy" sort="Best, Lucy" uniqKey="Best L" first="Lucy" last="Best">Lucy Best</name>
<affiliation wicri:level="2"><nlm:affiliation>St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Lorenzo, Lazaro" sort="Lorenzo, Lazaro" uniqKey="Lorenzo L" first="Lazaro" last="Lorenzo">Lazaro Lorenzo</name>
<affiliation wicri:level="3"><nlm:affiliation>Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, INSERM, Paris, France.</nlm:affiliation>
<country xml:lang="fr">France</country>
<wicri:regionArea>Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, INSERM, Paris</wicri:regionArea>
<placeName><region type="region">Île-de-France</region>
<region type="old region">Île-de-France</region>
<settlement type="city">Paris</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Casanova, Jean Laurent" sort="Casanova, Jean Laurent" uniqKey="Casanova J" first="Jean-Laurent" last="Casanova">Jean-Laurent Casanova</name>
<affiliation wicri:level="2"><nlm:affiliation>St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY</wicri:regionArea>
<placeName><region type="state">État de New York</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Wacker, Jochen" sort="Wacker, Jochen" uniqKey="Wacker J" first="Jochen" last="Wacker">Jochen Wacker</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Pathology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.</nlm:affiliation>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Department of Pathology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen</wicri:regionArea>
<placeName><settlement type="city">Erlangen</settlement>
<region type="land" nuts="1">Bavière</region>
<region type="district" nuts="2">District de Moyenne-Franconie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Bertz, Simone" sort="Bertz, Simone" uniqKey="Bertz S" first="Simone" last="Bertz">Simone Bertz</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Pathology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.</nlm:affiliation>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Department of Pathology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen</wicri:regionArea>
<placeName><settlement type="city">Erlangen</settlement>
<region type="land" nuts="1">Bavière</region>
<region type="district" nuts="2">District de Moyenne-Franconie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Agaimy, Abbas" sort="Agaimy, Abbas" uniqKey="Agaimy A" first="Abbas" last="Agaimy">Abbas Agaimy</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Pathology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.</nlm:affiliation>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Department of Pathology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen</wicri:regionArea>
<placeName><settlement type="city">Erlangen</settlement>
<region type="land" nuts="1">Bavière</region>
<region type="district" nuts="2">District de Moyenne-Franconie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Harrer, Thomas" sort="Harrer, Thomas" uniqKey="Harrer T" first="Thomas" last="Harrer">Thomas Harrer</name>
<affiliation wicri:level="3"><nlm:affiliation>Department for Internal Medicine III, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.</nlm:affiliation>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Department for Internal Medicine III, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen</wicri:regionArea>
<placeName><settlement type="city">Erlangen</settlement>
<region type="land" nuts="1">Bavière</region>
<region type="district" nuts="2">District de Moyenne-Franconie</region>
</placeName>
</affiliation>
</author>
</analytic>
<series><title level="j">Journal of clinical immunology</title>
<idno type="eISSN">1573-2592</idno>
<imprint><date when="2016" type="published">2016</date>
</imprint>
</series>
</biblStruct>
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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Adult</term>
<term>Calcium-Binding Proteins (genetics)</term>
<term>Calcium-Binding Proteins (metabolism)</term>
<term>Consanguinity</term>
<term>Craniofacial Abnormalities (diagnosis)</term>
<term>Craniofacial Abnormalities (genetics)</term>
<term>DNA Mutational Analysis</term>
<term>Female</term>
<term>Gene Expression Regulation (genetics)</term>
<term>Homozygote</term>
<term>Humans</term>
<term>Lymphangiectasis, Intestinal (diagnosis)</term>
<term>Lymphangiectasis, Intestinal (genetics)</term>
<term>Lymphedema (diagnosis)</term>
<term>Lymphedema (genetics)</term>
<term>Male</term>
<term>Mutation (genetics)</term>
<term>Pedigree</term>
<term>Siblings</term>
<term>Tumor Suppressor Proteins (genetics)</term>
<term>Tumor Suppressor Proteins (metabolism)</term>
<term>Turkey</term>
<term>Young Adult</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Adulte</term>
<term>Analyse de mutations d'ADN</term>
<term>Consanguinité</term>
<term>Femelle</term>
<term>Fratrie</term>
<term>Homozygote</term>
<term>Humains</term>
<term>Jeune adulte</term>
<term>Lymphangiectasie intestinale (diagnostic)</term>
<term>Lymphangiectasie intestinale (génétique)</term>
<term>Lymphoedème (diagnostic)</term>
<term>Lymphoedème (génétique)</term>
<term>Malformations crâniofaciales (diagnostic)</term>
<term>Malformations crâniofaciales (génétique)</term>
<term>Mutation (génétique)</term>
<term>Mâle</term>
<term>Pedigree</term>
<term>Protéines de liaison au calcium (génétique)</term>
<term>Protéines de liaison au calcium (métabolisme)</term>
<term>Protéines suppresseurs de tumeurs (génétique)</term>
<term>Protéines suppresseurs de tumeurs (métabolisme)</term>
<term>Régulation de l'expression des gènes (génétique)</term>
<term>Turquie</term>
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<keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Calcium-Binding Proteins</term>
<term>Tumor Suppressor Proteins</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Calcium-Binding Proteins</term>
<term>Tumor Suppressor Proteins</term>
</keywords>
<keywords scheme="MESH" qualifier="diagnosis" xml:lang="en"><term>Craniofacial Abnormalities</term>
<term>Lymphangiectasis, Intestinal</term>
<term>Lymphedema</term>
</keywords>
<keywords scheme="MESH" qualifier="diagnostic" xml:lang="fr"><term>Lymphangiectasie intestinale</term>
<term>Lymphoedème</term>
<term>Malformations crâniofaciales</term>
</keywords>
<keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Craniofacial Abnormalities</term>
<term>Gene Expression Regulation</term>
<term>Lymphangiectasis, Intestinal</term>
<term>Lymphedema</term>
<term>Mutation</term>
</keywords>
<keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Lymphangiectasie intestinale</term>
<term>Lymphoedème</term>
<term>Malformations crâniofaciales</term>
<term>Mutation</term>
<term>Protéines de liaison au calcium</term>
<term>Protéines suppresseurs de tumeurs</term>
<term>Régulation de l'expression des gènes</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Protéines de liaison au calcium</term>
<term>Protéines suppresseurs de tumeurs</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Adult</term>
<term>Consanguinity</term>
<term>DNA Mutational Analysis</term>
<term>Female</term>
<term>Homozygote</term>
<term>Humans</term>
<term>Male</term>
<term>Pedigree</term>
<term>Siblings</term>
<term>Turkey</term>
<term>Young Adult</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Adulte</term>
<term>Analyse de mutations d'ADN</term>
<term>Consanguinité</term>
<term>Femelle</term>
<term>Fratrie</term>
<term>Homozygote</term>
<term>Humains</term>
<term>Jeune adulte</term>
<term>Mâle</term>
<term>Pedigree</term>
<term>Turquie</term>
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<front><div type="abstract" xml:lang="en">Collagen and calcium-binding EGF domain-containing protein 1 (CCBE1) bi-allelic mutations have been associated with syndromes of widespread congenital lymphatic dysplasia, including Hennekam Syndrome (HS). HS is characterized by lymphedema, lymphangiectasia, and intellectual disability. CCBE1 encodes a putative extracellular matrix protein but the HS-causing mutations have not been studied biochemically. We report two HS siblings, born to consanguineous parents of Turkish ancestry, whose clinical phenotype also includes protein losing enteropathy, painful relapsing chylous ascites, and hypogammaglobulinemia. We identified by whole exome and Sanger sequencing the homozygous CCBE1 C174Y mutation in both siblings. This mutation had been previously reported in another HS kindred from the Netherlands. In over-expression studies, we found increased intracellular expression of all forms (monomers, dimers, trimers) of the CCBE1 C174Y mutant protein, by Western blot, despite mutant mRNA levels similar to wild-type (WT). In addition, we detected increased secretion of the mutant CCBE1 protein by ELISA. We further found the mutant and WT proteins to be evenly distributed in the cytoplasm, by immunofluorescence and confocal microscopy. Finally, we found a strong decrease of lymphatic vessels, with a corresponding diminished expression of CCBE1, by immunohistochemistry of the patients' intestinal biopsies. In contrast, mucosal blood vessels and muscularis mucosae showed normal CCBE1 staining. Our findings show that the mutant CCBE1 C174Y protein is not loss-of-function by loss-of-expression.</div>
</front>
</TEI>
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A Multiplex Kindred with Hennekam Syndrome due to Homozygosity for a CCBE1 Mutation that does not Prevent Protein Expression

A Multiplex Kindred with Hennekam Syndrome due to Homozygosity for a CCBE1 Mutation that does not Prevent Protein Expression

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