Identification and Functional Characterization of a Calcium-Sensing Receptor Mutation in an Infant with Familial Hypocalciuric Hypercalcemia
Identifieur interne : 000009 ( Pmc/Curation ); précédent : 000008; suivant : 000010Identification and Functional Characterization of a Calcium-Sensing Receptor Mutation in an Infant with Familial Hypocalciuric Hypercalcemia
Auteurs : Anna Papadopoulou [Grèce] ; Evangelia Gole [Grèce] ; Katerina Melachroinou [Grèce] ; Christos Meristoudis [Grèce] ; Tania Siahanidou [Grèce] ; Anastasios Papadimitriou [Grèce]Source :
- Journal of Clinical Research in Pediatric Endocrinology [ 1308-5727 ] ; 2016.
Abstract
Familial hypocalciuric hypercalcemia (FHH) is an autosomal dominant disorder, associated with inactivating mutations of the calcium-sensing receptor (CaSR). To evaluate the functional significance of a CaSR mutation, identified in a young infant who presented with hypercalcemia and hypocalciuria. The CaSR gene coding sequences were analyzed by polymerase chain reaction amplification and direct sequencing analysis. The mutation identified was introduced by site-directed mutagenesis into a wild-type (WT) CaSR plasmid, and human embryonic kidney 293 T cells were transfected with either the WT or mutant CaSR. The function of the mutated CaSR protein was analyzed by evaluating the free intracellular calcium [(Ca2+)i] response after challenge with extracellular calcium (Ca2+). We identified a heterozygous mutation c.772_773delGTinsA in exon 4 resulting in the substitution of amino acid valine (Val) with amino acid arginine (Arg) and the premature pause of the translation 46 amino acids later (Val258ArgfsTer47). Functional assay showed that cells transfected with the mutant CaSR had a significantly poorer response to extracellular Ca2+ stimulation compared with the WT. We have shown that the c.772_773delGTinsA mutation causes a significant alteration of CaSR function leading to features of FHH in an affected young infant since the first months of life.
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DOI: 10.4274/jcrpe.2800
PubMed: 27087013
PubMed Central: 5096500
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“Attikon”, Third Department of Pediatrics, Athens, Greece</nlm:aff><country xml:lang="fr">Grèce</country><wicri:regionArea> Athens University Medical School, University General Hospital “Attikon”, Third Department of Pediatrics, Athens</wicri:regionArea></affiliation></author><author><name sortKey="Melachroinou, Katerina" sort="Melachroinou, Katerina" uniqKey="Melachroinou K" first="Katerina" last="Melachroinou">Katerina Melachroinou</name><affiliation wicri:level="1"><nlm:aff id="A2"> Biomedical Research Foundation of the Academy of Athens, Division of Basic Neurosciences, Athens, Greece</nlm:aff><country xml:lang="fr">Grèce</country><wicri:regionArea> Biomedical Research Foundation of the Academy of Athens, Division of Basic Neurosciences, Athens</wicri:regionArea></affiliation></author><author><name sortKey="Meristoudis, Christos" sort="Meristoudis, Christos" uniqKey="Meristoudis C" first="Christos" last="Meristoudis">Christos Meristoudis</name><affiliation wicri:level="1"><nlm:aff id="A3"> University of Ioannina, Department of Biological Applications and Technology, Ioannina, Greece</nlm:aff><country xml:lang="fr">Grèce</country><wicri:regionArea> University of Ioannina, Department of Biological Applications and Technology, Ioannina</wicri:regionArea></affiliation></author><author><name sortKey="Siahanidou, Tania" sort="Siahanidou, Tania" uniqKey="Siahanidou T" first="Tania" last="Siahanidou">Tania Siahanidou</name><affiliation wicri:level="1"><nlm:aff id="A4"> Athens University Medical School, “Aghia Sophia” Children’s Hospital, First Department of Pediatrics, Athens, Greece</nlm:aff><country xml:lang="fr">Grèce</country><wicri:regionArea> Athens University Medical School, “Aghia Sophia” Children’s Hospital, First Department of Pediatrics, Athens</wicri:regionArea></affiliation></author><author><name sortKey="Papadimitriou, Anastasios" sort="Papadimitriou, Anastasios" uniqKey="Papadimitriou A" first="Anastasios" last="Papadimitriou">Anastasios 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wicri:step="Curation">000009</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Identification and Functional Characterization of a Calcium-Sensing Receptor Mutation in an Infant with Familial Hypocalciuric Hypercalcemia</title><author><name sortKey="Papadopoulou, Anna" sort="Papadopoulou, Anna" uniqKey="Papadopoulou A" first="Anna" last="Papadopoulou">Anna Papadopoulou</name><affiliation wicri:level="1"><nlm:aff id="A1"> Athens University Medical School, University General Hospital “Attikon”, Third Department of Pediatrics, Athens, Greece</nlm:aff><country xml:lang="fr">Grèce</country><wicri:regionArea> Athens University Medical School, University General Hospital “Attikon”, Third Department of Pediatrics, Athens</wicri:regionArea></affiliation></author><author><name sortKey="Gole, Evangelia" sort="Gole, Evangelia" uniqKey="Gole E" first="Evangelia" last="Gole">Evangelia Gole</name><affiliation wicri:level="1"><nlm:aff id="A1"> Athens University Medical School, University General Hospital “Attikon”, Third Department of Pediatrics, Athens, Greece</nlm:aff><country xml:lang="fr">Grèce</country><wicri:regionArea> Athens University Medical School, University General Hospital “Attikon”, Third Department of Pediatrics, Athens</wicri:regionArea></affiliation></author><author><name sortKey="Melachroinou, Katerina" sort="Melachroinou, Katerina" uniqKey="Melachroinou K" first="Katerina" last="Melachroinou">Katerina Melachroinou</name><affiliation wicri:level="1"><nlm:aff id="A2"> Biomedical Research Foundation of the Academy of Athens, Division of Basic Neurosciences, Athens, Greece</nlm:aff><country xml:lang="fr">Grèce</country><wicri:regionArea> Biomedical Research Foundation of the Academy of Athens, Division of Basic Neurosciences, Athens</wicri:regionArea></affiliation></author><author><name sortKey="Meristoudis, Christos" sort="Meristoudis, Christos" uniqKey="Meristoudis C" first="Christos" last="Meristoudis">Christos Meristoudis</name><affiliation wicri:level="1"><nlm:aff id="A3"> University of Ioannina, Department of Biological Applications and Technology, Ioannina, Greece</nlm:aff><country xml:lang="fr">Grèce</country><wicri:regionArea> University of Ioannina, Department of Biological Applications and Technology, Ioannina</wicri:regionArea></affiliation></author><author><name sortKey="Siahanidou, Tania" sort="Siahanidou, Tania" uniqKey="Siahanidou T" first="Tania" last="Siahanidou">Tania Siahanidou</name><affiliation wicri:level="1"><nlm:aff id="A4"> Athens University Medical School, “Aghia Sophia” Children’s Hospital, First Department of Pediatrics, Athens, Greece</nlm:aff><country xml:lang="fr">Grèce</country><wicri:regionArea> Athens University Medical School, “Aghia Sophia” Children’s Hospital, First Department of Pediatrics, Athens</wicri:regionArea></affiliation></author><author><name sortKey="Papadimitriou, Anastasios" sort="Papadimitriou, Anastasios" uniqKey="Papadimitriou A" first="Anastasios" last="Papadimitriou">Anastasios Papadimitriou</name><affiliation wicri:level="1"><nlm:aff id="A1"> Athens University Medical School, University General Hospital “Attikon”, Third Department of Pediatrics, Athens, Greece</nlm:aff><country xml:lang="fr">Grèce</country><wicri:regionArea> Athens University Medical School, University General Hospital “Attikon”, Third Department of Pediatrics, Athens</wicri:regionArea></affiliation></author></analytic><series><title level="j">Journal of Clinical Research in Pediatric Endocrinology</title><idno type="ISSN">1308-5727</idno><idno type="eISSN">1308-5735</idno><imprint><date when="2016">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Familial hypocalciuric hypercalcemia (FHH) is an autosomal dominant disorder, associated with inactivating mutations of the calcium-sensing receptor (CaSR). To evaluate the functional significance of a CaSR mutation, identified in a young infant who presented with hypercalcemia and hypocalciuria. The CaSR gene coding sequences were analyzed by polymerase chain reaction amplification and direct sequencing analysis. The mutation identified was introduced by site-directed mutagenesis into a wild-type (WT) CaSR plasmid, and human embryonic kidney 293 T cells were transfected with either the WT or mutant CaSR. The function of the mutated CaSR protein was analyzed by evaluating the free intracellular calcium [(Ca<sup>2+</sup>)<sub>i</sub>] response after challenge with extracellular calcium (Ca<sup>2+</sup>). We identified a heterozygous mutation c.772_773delGTinsA in exon 4 resulting in the substitution of amino acid valine (Val) with amino acid arginine (Arg) and the premature pause of the translation 46 amino acids later (Val258ArgfsTer47). Functional assay showed that cells transfected with the mutant CaSR had a significantly poorer response to extracellular Ca<sup>2+</sup> stimulation compared with the WT. We have shown that the c.772_773delGTinsA mutation causes a significant alteration of CaSR function leading to features of FHH in an affected young infant since the first months of life.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Brown, Em" uniqKey="Brown E">EM Brown</name></author><author><name sortKey="Gamba, G" uniqKey="Gamba G">G Gamba</name></author><author><name sortKey="Riccardi, D" uniqKey="Riccardi D">D Riccardi</name></author><author><name sortKey="Lombardi, M" uniqKey="Lombardi M">M Lombardi</name></author><author><name sortKey="Butters, R" uniqKey="Butters R">R Butters</name></author><author><name sortKey="Kifor, O" uniqKey="Kifor O">O Kifor</name></author><author><name sortKey="Sun, A" uniqKey="Sun A">A Sun</name></author><author><name sortKey="Hediger, Ma" uniqKey="Hediger M">MA Hediger</name></author><author><name sortKey="Lytton, J" uniqKey="Lytton J">J Lytton</name></author><author><name sortKey="Hebert, Sc" 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<front><journal-meta><journal-id journal-id-type="nlm-ta">J Clin Res Pediatr Endocrinol</journal-id><journal-id journal-id-type="iso-abbrev">J Clin Res Pediatr Endocrinol</journal-id><journal-id journal-id-type="publisher-id">JCRPE</journal-id><journal-title-group><journal-title>Journal of Clinical Research in Pediatric Endocrinology</journal-title></journal-title-group><issn pub-type="ppub">1308-5727</issn><issn pub-type="epub">1308-5735</issn><publisher><publisher-name>Galenos Publishing</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">27087013</article-id><article-id pub-id-type="pmc">5096500</article-id><article-id pub-id-type="doi">10.4274/jcrpe.2800</article-id><article-id pub-id-type="publisher-id">1788</article-id><article-categories><subj-group subj-group-type="heading"><subject>Case Report</subject></subj-group></article-categories><title-group><article-title>Identification and Functional Characterization of a Calcium-Sensing Receptor Mutation in an Infant with Familial Hypocalciuric Hypercalcemia</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Papadopoulou</surname><given-names>Anna</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="corresp" rid="COR1">*</xref></contrib><contrib contrib-type="author"><name><surname>Gole</surname><given-names>Evangelia</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Melachroinou</surname><given-names>Katerina</given-names></name><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Meristoudis</surname><given-names>Christos</given-names></name><xref ref-type="aff" rid="A3">3</xref></contrib><contrib contrib-type="author"><name><surname>Siahanidou</surname><given-names>Tania</given-names></name><xref ref-type="aff" rid="A4">4</xref></contrib><contrib contrib-type="author"><name><surname>Papadimitriou</surname><given-names>Anastasios</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib></contrib-group><aff id="A1"><label>1</label> Athens University Medical School, University General Hospital “Attikon”, Third Department of Pediatrics, Athens, Greece</aff><aff id="A2"><label>2</label> Biomedical Research Foundation of the Academy of Athens, Division of Basic Neurosciences, Athens, Greece</aff><aff id="A3"><label>3</label> University of Ioannina, Department of Biological Applications and Technology, Ioannina, Greece</aff><aff id="A4"><label>4</label> Athens University Medical School, “Aghia Sophia” Children’s Hospital, First Department of Pediatrics, Athens, Greece</aff><author-notes><corresp id="COR1">* Address for Correspondence: Athens University Medical School, University General Hospital “Attikon”, Third Department of Pediatrics, Athens, Greece Phone: +30 2105832228 E-mail: <email>anpapado@med.uoa.gr</email></corresp></author-notes><pub-date pub-type="ppub"><month>9</month><year>2016</year></pub-date><pub-date pub-type="epub"><day>1</day><month>9</month><year>2016</year></pub-date><volume>8</volume><issue>3</issue><fpage>341</fpage><lpage>346</lpage><history><date date-type="received"><day>31</day><month>12</month><year>2015</year></date><date date-type="accepted"><day>16</day><month>4</month><year>2016</year></date></history><permissions><copyright-statement>© Journal of Clinical Research in Pediatric Endocrinology, Published by Galenos Publishing.</copyright-statement><copyright-year>2016</copyright-year><license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by/2.5/"><license-p>This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.</license-p></license></permissions><abstract><p>Familial hypocalciuric hypercalcemia (FHH) is an autosomal dominant disorder, associated with inactivating mutations of the calcium-sensing receptor (CaSR). To evaluate the functional significance of a CaSR mutation, identified in a young infant who presented with hypercalcemia and hypocalciuria. The CaSR gene coding sequences were analyzed by polymerase chain reaction amplification and direct sequencing analysis. The mutation identified was introduced by site-directed mutagenesis into a wild-type (WT) CaSR plasmid, and human embryonic kidney 293 T cells were transfected with either the WT or mutant CaSR. The function of the mutated CaSR protein was analyzed by evaluating the free intracellular calcium [(Ca<sup>2+</sup>)<sub>i</sub>] response after challenge with extracellular calcium (Ca<sup>2+</sup>). We identified a heterozygous mutation c.772_773delGTinsA in exon 4 resulting in the substitution of amino acid valine (Val) with amino acid arginine (Arg) and the premature pause of the translation 46 amino acids later (Val258ArgfsTer47). Functional assay showed that cells transfected with the mutant CaSR had a significantly poorer response to extracellular Ca<sup>2+</sup> stimulation compared with the WT. We have shown that the c.772_773delGTinsA mutation causes a significant alteration of CaSR function leading to features of FHH in an affected young infant since the first months of life.</p></abstract><kwd-group><kwd>Familial hypocalciuric hypercalcemia</kwd><kwd>calcium-sensing receptor</kwd><kwd>calcium</kwd><kwd>hyperparathyroidism</kwd></kwd-group></article-meta></front><floats-group><fig id="f1" orientation="portrait" position="float"><label>Figure 1</label><caption><title>Sequencing analysis of CaSR gene (exon 4). Detection of c.772_773delGTinsA mutation in our proband</title></caption><graphic xlink:href="JCRPE-8-341-g1"></graphic></fig><fig id="f2" orientation="portrait" position="float"><label>Figure 2</label><caption><title>Alterations of Ca<sup>2+</sup>-evoked responses in the presence of CaSR mutation: (A) Steady-state levels of free cytosolic Ca<sup>2+</sup>. Representative Ca<sup>2+</sup> traces are shown in the left panel and quantitative analysis of the (Ca<sup>2+</sup>)<sub>i</sub> is depicted on the right panel. n=3; **p<0.01, comparing between wild-type and GT, using unpaired t-test. (B) Ca<sup>2+</sup> influx upon stimulation with CaCl<sub>2</sub>. Representative Ca<sup>2+</sup> measurements are shown in the left panel and quantitative estimation of (Ca<sup>2+</sup>)<sub>i</sub> increase (ΔnM), upon CaCl<sub>2</sub> stimulation is depicted on the right panel. n=3; *p<0.05, comparing between wild-type and GT using unpaired t-test. WT: wild-type</title></caption><graphic xlink:href="JCRPE-8-341-g2"></graphic></fig></floats-group></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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