LymphedemaV1, France, Analysis, bibRecord, 000094

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

Identifieur interne : 000094 ( France/Analysis ); précédent : 000093; suivant : 000095

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

Affiliations:

Links to Exploration step

PMC:4984268

Le document en format XML

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 Mutation that does not Prevent Protein Expression</title>
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<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>
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<term>Lymphangiectasis, Intestinal (genetics)</term>
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<term>Tumor Suppressor Proteins (genetics)</term>
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<term>Turkey</term>
<term>Young Adult</term>
</keywords>
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<term>Analyse de mutations d'ADN</term>
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<term>Fratrie</term>
<term>Homozygote</term>
<term>Humains</term>
<term>Jeune adulte</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 (génétique)</term>
<term>Protéines suppresseurs de tumeurs (métabolisme)</term>
<term>Régulation de l'expression des gènes (génétique)</term>
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</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>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<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>
<affiliations><list><country><li>Allemagne</li>
<li>France</li>
<li>États-Unis</li>
</country>
<region><li>Bavière</li>
<li>District de Moyenne-Franconie</li>
<li>Île-de-France</li>
</region>
<settlement><li>Erlangen</li>
<li>Paris</li>
</settlement>
</list>
<tree><country name="États-Unis"><noRegion><name sortKey="Jackson, Carolyn C" sort="Jackson, Carolyn C" uniqKey="Jackson C" first="Carolyn C." last="Jackson">Carolyn C. Jackson</name>
</noRegion>
<name sortKey="Best, Lucy" sort="Best, Lucy" uniqKey="Best L" first="Lucy" last="Best">Lucy Best</name>
<name sortKey="Casanova, Jean Laurent" sort="Casanova, Jean Laurent" uniqKey="Casanova J" first="Jean-Laurent" last="Casanova">Jean-Laurent Casanova</name>
<name sortKey="Casanova, Jean Laurent" sort="Casanova, Jean Laurent" uniqKey="Casanova J" first="Jean-Laurent" last="Casanova">Jean-Laurent Casanova</name>
<name sortKey="Jackson, Carolyn C" sort="Jackson, Carolyn C" uniqKey="Jackson C" first="Carolyn C." last="Jackson">Carolyn C. Jackson</name>
</country>
<country name="France"><region name="Île-de-France"><name sortKey="Lorenzo, Lazaro" sort="Lorenzo, Lazaro" uniqKey="Lorenzo L" first="Lazaro" last="Lorenzo">Lazaro Lorenzo</name>
</region>
<name sortKey="Casanova, Jean Laurent" sort="Casanova, Jean Laurent" uniqKey="Casanova J" first="Jean-Laurent" last="Casanova">Jean-Laurent Casanova</name>
<name sortKey="Casanova, Jean Laurent" sort="Casanova, Jean Laurent" uniqKey="Casanova J" first="Jean-Laurent" last="Casanova">Jean-Laurent Casanova</name>
<name sortKey="Casanova, Jean Laurent" sort="Casanova, Jean Laurent" uniqKey="Casanova J" first="Jean-Laurent" last="Casanova">Jean-Laurent Casanova</name>
</country>
<country name="Allemagne"><region name="Bavière"><name sortKey="Wacker, Jochen" sort="Wacker, Jochen" uniqKey="Wacker J" first="Jochen" last="Wacker">Jochen Wacker</name>
</region>
<name sortKey="Agaimy, Abbas" sort="Agaimy, Abbas" uniqKey="Agaimy A" first="Abbas" last="Agaimy">Abbas Agaimy</name>
<name sortKey="Bertz, Simone" sort="Bertz, Simone" uniqKey="Bertz S" first="Simone" last="Bertz">Simone Bertz</name>
<name sortKey="Harrer, Thomas" sort="Harrer, Thomas" uniqKey="Harrer T" first="Thomas" last="Harrer">Thomas Harrer</name>
</country>
</tree>
</affiliations>
</record>

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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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