Atypical juvenile presentation of GM2 gangliosidosis AB in a patient compound-heterozygote for c.259G > T and c.164C > T mutations in the GM2A gene☆
Identifieur interne : 000369 ( Pmc/Curation ); précédent : 000368; suivant : 000370Atypical juvenile presentation of GM2 gangliosidosis AB in a patient compound-heterozygote for c.259G > T and c.164C > T mutations in the GM2A gene☆
Auteurs : Carla Martins [Canada] ; Catherine Brunel-Guitton [Canada] ; Anne Lortie [Canada] ; France Gauvin [Canada] ; Carlos R. Morales [Canada] ; Grant A. Mitchell [Canada] ; Alexey V. Pshezhetsky [Canada]Source :
- Molecular Genetics and Metabolism Reports [ 2214-4269 ] ; 2017.
Abstract
GM2-gangliosidosis, AB variant is an extremely rare autosomal recessive inherited disorder caused by mutations in the
Url:
DOI: 10.1016/j.ymgmr.2017.01.017
PubMed: 28417072
PubMed Central: 5388932
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Atypical juvenile presentation of G<sub>M2</sub> gangliosidosis AB in a patient compound-heterozygote for c.259G > T and c.164C > T mutations in the <italic>GM2A</italic> gene<sup><xref ref-type="fn" rid="d31e166">☆</xref></sup></title><author><name sortKey="Martins, Carla" sort="Martins, Carla" uniqKey="Martins C" first="Carla" last="Martins">Carla Martins</name><affiliation wicri:level="1"><nlm:aff id="af0005">CHU Ste-Justine, University of Montreal, Montreal, QC, Canada</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>CHU Ste-Justine, University of Montreal, Montreal, QC</wicri:regionArea></affiliation></author><author><name sortKey="Brunel Guitton, Catherine" sort="Brunel Guitton, Catherine" uniqKey="Brunel Guitton C" first="Catherine" last="Brunel-Guitton">Catherine Brunel-Guitton</name><affiliation wicri:level="1"><nlm:aff id="af0005">CHU Ste-Justine, University of Montreal, Montreal, QC, Canada</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>CHU Ste-Justine, University of Montreal, Montreal, QC</wicri:regionArea></affiliation></author><author><name sortKey="Lortie, Anne" sort="Lortie, Anne" uniqKey="Lortie A" first="Anne" last="Lortie">Anne Lortie</name><affiliation wicri:level="1"><nlm:aff id="af0005">CHU Ste-Justine, University of Montreal, Montreal, QC, Canada</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>CHU Ste-Justine, University of Montreal, Montreal, QC</wicri:regionArea></affiliation></author><author><name sortKey="Gauvin, France" sort="Gauvin, France" uniqKey="Gauvin F" first="France" last="Gauvin">France Gauvin</name><affiliation wicri:level="1"><nlm:aff id="af0005">CHU Ste-Justine, University of Montreal, Montreal, QC, Canada</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>CHU Ste-Justine, University of Montreal, Montreal, QC</wicri:regionArea></affiliation></author><author><name sortKey="Morales, Carlos R" sort="Morales, Carlos R" uniqKey="Morales C" first="Carlos R." last="Morales">Carlos R. Morales</name><affiliation wicri:level="1"><nlm:aff id="af0010">Department of Anatomy and Cell Biology, McGill University, Montreal, QC, Canada</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Anatomy and Cell Biology, McGill University, Montreal, QC</wicri:regionArea></affiliation></author><author><name sortKey="Mitchell, Grant A" sort="Mitchell, Grant A" uniqKey="Mitchell G" first="Grant A." last="Mitchell">Grant A. Mitchell</name><affiliation wicri:level="1"><nlm:aff id="af0005">CHU Ste-Justine, University of Montreal, Montreal, QC, Canada</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>CHU Ste-Justine, University of Montreal, Montreal, QC</wicri:regionArea></affiliation></author><author><name sortKey="Pshezhetsky, Alexey V" sort="Pshezhetsky, Alexey V" uniqKey="Pshezhetsky A" first="Alexey V." last="Pshezhetsky">Alexey V. Pshezhetsky</name><affiliation wicri:level="1"><nlm:aff id="af0005">CHU Ste-Justine, University of Montreal, Montreal, QC, Canada</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>CHU Ste-Justine, University of Montreal, Montreal, QC</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="af0010">Department of Anatomy and Cell Biology, McGill University, Montreal, QC, Canada</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Anatomy and Cell Biology, McGill University, Montreal, QC</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">28417072</idno><idno type="pmc">5388932</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5388932</idno><idno type="RBID">PMC:5388932</idno><idno type="doi">10.1016/j.ymgmr.2017.01.017</idno><date when="2017">2017</date><idno type="wicri:Area/Pmc/Corpus">000369</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000369</idno><idno type="wicri:Area/Pmc/Curation">000369</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000369</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Atypical juvenile presentation of G<sub>M2</sub> gangliosidosis AB in a patient compound-heterozygote for c.259G > T and c.164C > T mutations in the <italic>GM2A</italic> gene<sup><xref ref-type="fn" rid="d31e166">☆</xref></sup></title><author><name sortKey="Martins, Carla" sort="Martins, Carla" uniqKey="Martins C" first="Carla" last="Martins">Carla Martins</name><affiliation wicri:level="1"><nlm:aff id="af0005">CHU Ste-Justine, University of Montreal, Montreal, QC, Canada</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>CHU Ste-Justine, University of Montreal, Montreal, QC</wicri:regionArea></affiliation></author><author><name sortKey="Brunel Guitton, Catherine" sort="Brunel Guitton, Catherine" uniqKey="Brunel Guitton C" first="Catherine" last="Brunel-Guitton">Catherine Brunel-Guitton</name><affiliation wicri:level="1"><nlm:aff id="af0005">CHU Ste-Justine, University of Montreal, Montreal, QC, Canada</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>CHU Ste-Justine, University of Montreal, Montreal, QC</wicri:regionArea></affiliation></author><author><name sortKey="Lortie, Anne" sort="Lortie, Anne" uniqKey="Lortie A" first="Anne" last="Lortie">Anne Lortie</name><affiliation wicri:level="1"><nlm:aff id="af0005">CHU Ste-Justine, University of Montreal, Montreal, QC, Canada</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>CHU Ste-Justine, University of Montreal, Montreal, QC</wicri:regionArea></affiliation></author><author><name sortKey="Gauvin, France" sort="Gauvin, France" uniqKey="Gauvin F" first="France" last="Gauvin">France Gauvin</name><affiliation wicri:level="1"><nlm:aff id="af0005">CHU Ste-Justine, University of Montreal, Montreal, QC, Canada</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>CHU Ste-Justine, University of Montreal, Montreal, QC</wicri:regionArea></affiliation></author><author><name sortKey="Morales, Carlos R" sort="Morales, Carlos R" uniqKey="Morales C" first="Carlos R." last="Morales">Carlos R. Morales</name><affiliation wicri:level="1"><nlm:aff id="af0010">Department of Anatomy and Cell Biology, McGill University, Montreal, QC, Canada</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Anatomy and Cell Biology, McGill University, Montreal, QC</wicri:regionArea></affiliation></author><author><name sortKey="Mitchell, Grant A" sort="Mitchell, Grant A" uniqKey="Mitchell G" first="Grant A." last="Mitchell">Grant A. Mitchell</name><affiliation wicri:level="1"><nlm:aff id="af0005">CHU Ste-Justine, University of Montreal, Montreal, QC, Canada</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>CHU Ste-Justine, University of Montreal, Montreal, QC</wicri:regionArea></affiliation></author><author><name sortKey="Pshezhetsky, Alexey V" sort="Pshezhetsky, Alexey V" uniqKey="Pshezhetsky A" first="Alexey V." last="Pshezhetsky">Alexey V. Pshezhetsky</name><affiliation wicri:level="1"><nlm:aff id="af0005">CHU Ste-Justine, University of Montreal, Montreal, QC, Canada</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>CHU Ste-Justine, University of Montreal, Montreal, QC</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="af0010">Department of Anatomy and Cell Biology, McGill University, Montreal, QC, Canada</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Anatomy and Cell Biology, McGill University, Montreal, QC</wicri:regionArea></affiliation></author></analytic><series><title level="j">Molecular Genetics and Metabolism Reports</title><idno type="eISSN">2214-4269</idno><imprint><date when="2017">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>G<sub>M2</sub>-gangliosidosis, AB variant is an extremely rare autosomal recessive inherited disorder caused by mutations in the <italic>GM2A</italic> gene that encodes G<sub>M2</sub> ganglioside activator protein (GM2AP). GM2AP is necessary for solubilisation of G<sub>M2</sub> ganglioside in endolysosomes and its presentation to β-hexosaminidase A. Conversely GM2AP deficiency impairs lysosomal catabolism of G<sub>M2</sub> ganglioside, leading to its storage in cells and tissues. We describe a 9-year-old child with an unusual juvenile clinical onset of G<sub>M2</sub>-gangliosidosis AB. At the age of 3 years he presented with global developmental delay, progressive epilepsy, intellectual disability, axial hypertonia, spasticity, seizures and ataxia, but without the macular cherry-red spots typical for G<sub>M2</sub> gangliosidosis. Brain MRI detected a rapid onset of diffuse atrophy, whereas whole exome sequencing showed that the patient is a compound heterozygote for two mutations in <italic>GM2A</italic>: a novel nonsense mutation, c.259G > T (p.E87X) and a missense mutation c.164C > T (p.P55L) that was recently identified in homozygosity in patients of a Saudi family with a progressive chorea-dementia syndrome. Western blot analysis showed an absence of GM2AP in cultured fibroblasts from the patient, suggesting that both mutations interfere with the synthesis and/or folding of the protein. Finally, impaired catabolism of G<sub>M2</sub> ganglioside in the patient's fibroblasts was demonstrated by metabolic labeling with fluorescently labeled G<sub>M1</sub> ganglioside and by immunohistochemistry with anti-G<sub>M2</sub> and anti-G<sub>M3</sub> antibodies. Our observation expands the molecular and clinical spectrum of molecular defects linked to G<sub>M2</sub>-gangliosidosis and suggests novel diagnostic approach by whole exome sequencing and perhaps ganglioside analysis in cultured patient's cells.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Sandhoff, K" uniqKey="Sandhoff K">K. Sandhoff</name></author><author><name sortKey="Harzer, K" uniqKey="Harzer K">K. Harzer</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Burkhardt, J K" uniqKey="Burkhardt J">J.K. Burkhardt</name></author><author><name sortKey="Huttler, S" uniqKey="Huttler S">S. Huttler</name></author><author><name sortKey="Klein, A" uniqKey="Klein A">A. Klein</name></author><author><name sortKey="Mobius, W" uniqKey="Mobius W">W. Mobius</name></author><author><name sortKey="Habermann, A" uniqKey="Habermann A">A. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Mol Genet Metab Rep</journal-id><journal-id journal-id-type="iso-abbrev">Mol Genet Metab Rep</journal-id><journal-title-group><journal-title>Molecular Genetics and Metabolism Reports</journal-title></journal-title-group><issn pub-type="epub">2214-4269</issn><publisher><publisher-name>Elsevier</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">28417072</article-id><article-id pub-id-type="pmc">5388932</article-id><article-id pub-id-type="publisher-id">S2214-4269(16)30142-2</article-id><article-id pub-id-type="doi">10.1016/j.ymgmr.2017.01.017</article-id><article-categories><subj-group subj-group-type="heading"><subject>Case Report</subject></subj-group></article-categories><title-group><article-title>Atypical juvenile presentation of G<sub>M2</sub> gangliosidosis AB in a patient compound-heterozygote for c.259G > T and c.164C > T mutations in the <italic>GM2A</italic> gene<sup><xref ref-type="fn" rid="d31e166">☆</xref></sup></article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Martins</surname><given-names>Carla</given-names></name><xref rid="af0005" ref-type="aff">a</xref></contrib><contrib contrib-type="author"><name><surname>Brunel-Guitton</surname><given-names>Catherine</given-names></name><xref rid="af0005" ref-type="aff">a</xref></contrib><contrib contrib-type="author"><name><surname>Lortie</surname><given-names>Anne</given-names></name><xref rid="af0005" ref-type="aff">a</xref></contrib><contrib contrib-type="author"><name><surname>Gauvin</surname><given-names>France</given-names></name><xref rid="af0005" ref-type="aff">a</xref></contrib><contrib contrib-type="author"><name><surname>Morales</surname><given-names>Carlos R.</given-names></name><xref rid="af0010" ref-type="aff">b</xref></contrib><contrib contrib-type="author"><name><surname>Mitchell</surname><given-names>Grant A.</given-names></name><xref rid="af0005" ref-type="aff">a</xref><xref rid="fn0005" ref-type="fn">1</xref></contrib><contrib contrib-type="author"><name><surname>Pshezhetsky</surname><given-names>Alexey V.</given-names></name><email>alexei.pchejetski@umontreal.ca</email><xref rid="af0005" ref-type="aff">a</xref><xref rid="af0010" ref-type="aff">b</xref><xref rid="cr0005" ref-type="corresp">⁎</xref><xref rid="fn0005" ref-type="fn">1</xref></contrib></contrib-group><aff id="af0005"><label>a</label>CHU Ste-Justine, University of Montreal, Montreal, QC, Canada</aff><aff id="af0010"><label>b</label>Department of Anatomy and Cell Biology, McGill University, Montreal, QC, Canada</aff><author-notes><corresp id="cr0005"><label>⁎</label>Corresponding author at: Service de génétique médicale, CHU Sainte-Justine, 3175 Côte Ste-Catherine, Montréal, QC H3T 1C5, Canada.Service de génétique médicaleCHU Sainte-Justine3175 Côte Ste-CatherineMontréalQCH3T 1C5Canada <email>alexei.pchejetski@umontreal.ca</email></corresp><fn id="fn0005"><label>1</label><p id="np0010">Equally contributed as senior authors.</p></fn></author-notes><pub-date pub-type="pmc-release"><day>07</day><month>4</month><year>2017</year></pub-date><pmc-comment> PMC Release delay is 0 months and 0 days and was based on .</pmc-comment>
<pub-date pub-type="collection"><month>6</month><year>2017</year></pub-date><pub-date pub-type="epub"><day>07</day><month>4</month><year>2017</year></pub-date><volume>11</volume><fpage>24</fpage><lpage>29</lpage><history><date date-type="received"><day>28</day><month>12</month><year>2016</year></date><date date-type="rev-recd"><day>18</day><month>1</month><year>2017</year></date><date date-type="accepted"><day>18</day><month>1</month><year>2017</year></date></history><permissions><copyright-statement>© 2017 The Authors</copyright-statement><copyright-year>2017</copyright-year><license license-type="CC BY-NC-ND" xlink:href="http://creativecommons.org/licenses/by-nc-nd/4.0/"><license-p>This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).</license-p></license></permissions><abstract id="ab0005"><p>G<sub>M2</sub>-gangliosidosis, AB variant is an extremely rare autosomal recessive inherited disorder caused by mutations in the <italic>GM2A</italic> gene that encodes G<sub>M2</sub> ganglioside activator protein (GM2AP). GM2AP is necessary for solubilisation of G<sub>M2</sub> ganglioside in endolysosomes and its presentation to β-hexosaminidase A. Conversely GM2AP deficiency impairs lysosomal catabolism of G<sub>M2</sub> ganglioside, leading to its storage in cells and tissues. We describe a 9-year-old child with an unusual juvenile clinical onset of G<sub>M2</sub>-gangliosidosis AB. At the age of 3 years he presented with global developmental delay, progressive epilepsy, intellectual disability, axial hypertonia, spasticity, seizures and ataxia, but without the macular cherry-red spots typical for G<sub>M2</sub> gangliosidosis. Brain MRI detected a rapid onset of diffuse atrophy, whereas whole exome sequencing showed that the patient is a compound heterozygote for two mutations in <italic>GM2A</italic>: a novel nonsense mutation, c.259G > T (p.E87X) and a missense mutation c.164C > T (p.P55L) that was recently identified in homozygosity in patients of a Saudi family with a progressive chorea-dementia syndrome. Western blot analysis showed an absence of GM2AP in cultured fibroblasts from the patient, suggesting that both mutations interfere with the synthesis and/or folding of the protein. Finally, impaired catabolism of G<sub>M2</sub> ganglioside in the patient's fibroblasts was demonstrated by metabolic labeling with fluorescently labeled G<sub>M1</sub> ganglioside and by immunohistochemistry with anti-G<sub>M2</sub> and anti-G<sub>M3</sub> antibodies. Our observation expands the molecular and clinical spectrum of molecular defects linked to G<sub>M2</sub>-gangliosidosis and suggests novel diagnostic approach by whole exome sequencing and perhaps ganglioside analysis in cultured patient's cells.</p></abstract><kwd-group id="ks0005"><title>Keywords</title><kwd>Gangliosidosis</kwd><kwd>G<sub>M2</sub> ganglioside</kwd><kwd>G<sub>M2</sub> ganglioside activator protein</kwd><kwd>Lysosomal storage disease</kwd></kwd-group></article-meta></front><floats-group><fig id="f0005"><label>Fig. 1</label><caption><p>GM2AP is not detected in the patient's cultured fibroblasts by Western blot.</p><p>Either 40 or 50 μg of total protein extracted from cultured fibroblasts of the patient or normal healthy controls (N = 2) were resolved on SDS PAGE gels, transferred to nitrocellulose membrane and hybridized with anti-GM2AP antibody. A mature ~ 20 kDa GM2AP band was detected in control fibroblasts but not in the patient's fibroblasts. The two bands detected in the protein extract of Cos7 cells transfected with a plasmid encoding GM2AP correspond to the mature ~ 20 kDa protein and its ~ 22 kDa precursor. α-Tubulin was used as a loading control.</p></caption><alt-text id="al0005">Fig. 1</alt-text><graphic xlink:href="gr1"></graphic></fig><fig id="f0010"><label>Fig. 2</label><caption><p>Thin-layer chromatography of fluorescently labeled gangliosides reveals accumulation of G<sub>M2</sub> ganglioside in the patient's cultured fibroblasts.</p><p>Fibroblasts of the patient or a normal healthy control subject were cultured in DMEM containing 1.45 μM of fluorescently labeled BODIPY® FL C5 G<sub>M1</sub> ganglioside for 72 h. Total lipids were extracted from cell pellets with 1:1 chloroform/methanol mixture and the gangliosides were separated from neutral lipids and analysed by TLC on silica plates.</p><p>(A) The fluorescence image of the TLC plate acquired on G:Box Chemi XQR system. The position of fluorescent G<sub>M1</sub> ganglioside used as a standard is shown.</p><p>(B) G<sub>M1</sub> and G<sub>M2</sub> ganglioside bands were quantified in control and patient's fibroblasts by ImageJ software.</p></caption><alt-text id="al0010">Fig. 2</alt-text><graphic xlink:href="gr2"></graphic></fig><fig id="f0015"><label>Fig. 3</label><caption><p>Increased lysosomal G<sub>M2</sub> and reduced G<sub>M3</sub> ganglioside in the patient's cultured fibroblasts.</p><p>(A) Fibroblasts from the patient and two normal healthy controls cultured on glass coverslips were fixed and stained with monoclonal humanized anti-G<sub>M2</sub> and mouse anti-LAMP-2 antibodies followed by anti-human IgG Alexa 488-labeled (green) and anti-mouse IgG Alexa 555-labeled (red) secondary antibodies. Nuclei were stained with Draq5 (blue). The patient's fibroblasts show a higher intensity of G<sub>M2</sub> staining (green) than control fibroblasts and increased co-localization of G<sub>M2</sub> and LAMP-2 staining.</p><p>(B) Fibroblasts from the patient and two normal healthy controls were stained with monoclonal mouse anti-G<sub>M3</sub> antibody followed by anti-mouse IgG Alexa-555-labeled secondary antibody (red). Nuclei were stained with Draq5 (blue).</p><p>The images were acquired in a Leica SP8 confocal microscope with a 63 × objective. Bar represents 10 μM. The panels show representative images of at least 40 studied for each cell type.</p><p>(C) Mean G<sub>M2</sub> and G<sub>M3</sub> staining intensity and a fraction of G<sub>M2</sub>-positive cells in control and patient's fibroblasts. Mean staining intensities per μm<sup>2</sup> were measured with ImageJ software. Data show mean (± SEM) of individual values measured for 35 randomly selected cells. **<italic>P</italic> < 0.01, *<italic>P</italic> < 0.05 in unpaired two-tailed <italic>t</italic>-test. G<sub>M2</sub>-positive cells were manually counted in three randomly selected microscope fields (~ 150 cells each). Data show mean values (± SEM) of 3 independent experiments. *<italic>P</italic> < 0.05 in unpaired two-tailed <italic>t</italic>-test. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)</p></caption><alt-text id="al0015">Fig. 3</alt-text><graphic xlink:href="gr3"></graphic></fig></floats-group></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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