Inborn Error of Cobalamin Metabolism Associated with the Intracellular Accumulation of Transcobalamin‐Bound Cobalamin and Mutations in ZNF143, Which Codes for a Transcriptional Activator
Identifieur interne : 000E09 ( Main/Exploration ); précédent : 000E08; suivant : 000E10Inborn Error of Cobalamin Metabolism Associated with the Intracellular Accumulation of Transcobalamin‐Bound Cobalamin and Mutations in ZNF143, Which Codes for a Transcriptional Activator
Auteurs : Mihaela Pupavac [Canada] ; David Watkins [Canada] ; Francis Petrella [Canada] ; Somayyeh Fahiminiya [Canada] ; Alexandre Janer [Canada] ; Warren Cheung [Canada] ; Anne-Claude Gingras [Canada] ; Tomi Pastinen [Canada] ; Joseph Muenzer [États-Unis] ; Jacek Majewski [Canada] ; Eric A. Shoubridge [Canada] ; David S. Rosenblatt [Canada]Source :
- Human Mutation [ 1059-7794 ] ; 2016-09.
Abstract
Vitamin B12 (cobalamin, Cbl) cofactors adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl) are required for the activity of the enzymes methylmalonyl‐CoA mutase (MCM) and methionine synthase (MS). Inborn errors of Cbl metabolism are rare Mendelian disorders associated with hematological and neurological manifestations, and elevations of methylmalonic acid and/or homocysteine in the blood and urine. We describe a patient whose fibroblasts had decreased functional activity of MCM and MS and decreased synthesis of AdoCbl and MeCbl (3.4% and 1.0% of cellular Cbl, respectively). The defect in cultured patient fibroblasts complemented those from all known complementation groups. Patient cells accumulated transcobalamin‐bound–Cbl, a complex which usually dissociates in the lysosome to release free Cbl. Whole‐exome sequencing identified putative disease‐causing variants c.851T>G (p.L284*) and c.1019C>T (p.T340I) in transcription factor ZNF143. Proximity biotinylation analysis confirmed the interaction between ZNF143 and HCFC1, a protein that regulates expression of the Cbl trafficking enzyme MMACHC. qRT‐PCR analysis revealed low MMACHC expression levels both in patient fibroblasts, and in control fibroblasts incubated with ZNF143 siRNA.
Mutations in a DNA regulating gene, ZNF143, cause a previously undescribed inherited disorder of vitamin B12 (cobalamin) metabolism. These mutations cause an accumulation of transcobalamin‐bound cobalamin within the cells, as well as decreased expression of MMACHC, a cobalamin trafficking protein.
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DOI: 10.1002/humu.23037
Affiliations:
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Rosenblatt</name><affiliation wicri:level="4"><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Human Genetics, McGill University, Quebec, Montreal</wicri:regionArea><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName><orgName type="university">Université McGill</orgName></affiliation><affiliation wicri:level="1"><country wicri:rule="url">Canada</country></affiliation></author></analytic><monogr></monogr><series><title level="j" type="main">Human Mutation</title><title level="j" type="alt">HUMAN MUTATION</title><idno type="ISSN">1059-7794</idno><idno type="eISSN">1098-1004</idno><imprint><biblScope unit="vol">37</biblScope><biblScope unit="issue">9</biblScope><biblScope unit="page" from="976">976</biblScope><biblScope unit="page" to="982">982</biblScope><biblScope unit="page-count">7</biblScope><date type="published" when="2016-09">2016-09</date></imprint><idno type="ISSN">1059-7794</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">1059-7794</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract">Vitamin B12 (cobalamin, Cbl) cofactors adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl) are required for the activity of the enzymes methylmalonyl‐CoA mutase (MCM) and methionine synthase (MS). Inborn errors of Cbl metabolism are rare Mendelian disorders associated with hematological and neurological manifestations, and elevations of methylmalonic acid and/or homocysteine in the blood and urine. We describe a patient whose fibroblasts had decreased functional activity of MCM and MS and decreased synthesis of AdoCbl and MeCbl (3.4% and 1.0% of cellular Cbl, respectively). The defect in cultured patient fibroblasts complemented those from all known complementation groups. Patient cells accumulated transcobalamin‐bound–Cbl, a complex which usually dissociates in the lysosome to release free Cbl. Whole‐exome sequencing identified putative disease‐causing variants c.851T>G (p.L284*) and c.1019C>T (p.T340I) in transcription factor ZNF143. Proximity biotinylation analysis confirmed the interaction between ZNF143 and HCFC1, a protein that regulates expression of the Cbl trafficking enzyme MMACHC. qRT‐PCR analysis revealed low MMACHC expression levels both in patient fibroblasts, and in control fibroblasts incubated with ZNF143 siRNA.</div><div type="abstract" xml:lang="en">Mutations in a DNA regulating gene, ZNF143, cause a previously undescribed inherited disorder of vitamin B12 (cobalamin) metabolism. These mutations cause an accumulation of transcobalamin‐bound cobalamin within the cells, as well as decreased expression of MMACHC, a cobalamin trafficking protein.</div></front></TEI><affiliations><list><country><li>Canada</li><li>États-Unis</li></country><region><li>Ontario</li><li>Québec</li></region><settlement><li>Montréal</li><li>Toronto</li></settlement><orgName><li>Université McGill</li><li>Université de Toronto</li></orgName></list><tree><country name="Canada"><region name="Québec"><name sortKey="Pupavac, Mihaela" sort="Pupavac, Mihaela" uniqKey="Pupavac M" first="Mihaela" last="Pupavac">Mihaela Pupavac</name></region><name sortKey="Cheung, Warren" sort="Cheung, Warren" uniqKey="Cheung W" first="Warren" last="Cheung">Warren Cheung</name><name sortKey="Fahiminiya, Somayyeh" sort="Fahiminiya, Somayyeh" uniqKey="Fahiminiya S" first="Somayyeh" last="Fahiminiya">Somayyeh Fahiminiya</name><name sortKey="Fahiminiya, Somayyeh" sort="Fahiminiya, Somayyeh" uniqKey="Fahiminiya S" first="Somayyeh" last="Fahiminiya">Somayyeh Fahiminiya</name><name sortKey="Gingras, Anne Laude" sort="Gingras, Anne Laude" uniqKey="Gingras A" first="Anne-Claude" last="Gingras">Anne-Claude Gingras</name><name sortKey="Janer, Alexandre" sort="Janer, Alexandre" uniqKey="Janer A" first="Alexandre" last="Janer">Alexandre Janer</name><name sortKey="Majewski, Jacek" sort="Majewski, Jacek" uniqKey="Majewski J" first="Jacek" last="Majewski">Jacek Majewski</name><name sortKey="Majewski, Jacek" sort="Majewski, Jacek" uniqKey="Majewski J" first="Jacek" last="Majewski">Jacek Majewski</name><name sortKey="Pastinen, Tomi" sort="Pastinen, Tomi" uniqKey="Pastinen T" first="Tomi" last="Pastinen">Tomi Pastinen</name><name sortKey="Pastinen, Tomi" sort="Pastinen, Tomi" uniqKey="Pastinen T" first="Tomi" last="Pastinen">Tomi Pastinen</name><name sortKey="Petrella, Francis" sort="Petrella, Francis" uniqKey="Petrella F" first="Francis" last="Petrella">Francis Petrella</name><name sortKey="Rosenblatt, David S" sort="Rosenblatt, David S" uniqKey="Rosenblatt D" first="David S." last="Rosenblatt">David S. Rosenblatt</name><name sortKey="Rosenblatt, David S" sort="Rosenblatt, David S" uniqKey="Rosenblatt D" first="David S." last="Rosenblatt">David S. Rosenblatt</name><name sortKey="Shoubridge, Eric A" sort="Shoubridge, Eric A" uniqKey="Shoubridge E" first="Eric A." last="Shoubridge">Eric A. Shoubridge</name><name sortKey="Watkins, David" sort="Watkins, David" uniqKey="Watkins D" first="David" last="Watkins">David Watkins</name></country><country name="États-Unis"><noRegion><name sortKey="Muenzer, Joseph" sort="Muenzer, Joseph" uniqKey="Muenzer J" first="Joseph" last="Muenzer">Joseph Muenzer</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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