Novel variant in the CNNM2 gene associated with dominant hypomagnesemia
The maintenance of magnesium (Mg2+) homeostasis is essential for human life. The Cystathionine-β-synthase (CBS)-pair domain divalent metal cation transport mediators (CNNMs) have been described to be involved in maintaining Mg2+ homeostasis. Among these CNNMs, CNNM2 is expressed in the basolateral m...
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| creator | García-Castaño, Alejandro Madariaga, Leire Antón-Gamero, Montserrat Mejia, Natalia Ponce, Jenny Gómez-Conde, Sara Pérez de Nanclares, Gustavo De la Hoz, Ana Belén Martínez, Rosa Saso, Laura Martínez de LaPiscina, Idoia Urrutia, Inés Velasco, Olaia Aguayo, Aníbal Castaño, Luis Gaztambide, Sonia |
| description | The maintenance of magnesium (Mg2+) homeostasis is essential for human life. The Cystathionine-β-synthase (CBS)-pair domain divalent metal cation transport mediators (CNNMs) have been described to be involved in maintaining Mg2+ homeostasis. Among these CNNMs, CNNM2 is expressed in the basolateral membrane of the kidney tubules where it is involved in Mg2+ reabsorption. A total of four patients, two of them with a suspected disorder of calcium metabolism, and two patients with a clinical diagnosis of primary tubulopathy were screened for mutations by Next-Generation Sequencing (NGS). We found one novel likely pathogenic variant in the heterozygous state (c.2384C>A; p.(Ser795*)) in the CNNM2 gene in a family with a suspected disorder of calcium metabolism. In this family, hypomagnesemia was indirectly discovered. Moreover, we observed three novel variants of uncertain significance in heterozygous state in the other three patients (c.557G>C; p.(Ser186Thr), c.778A>T; p.(Ile260Phe), and c.1003G>A; p.(Asp335Asn)). Our study shows the utility of Next-Generation Sequencing in unravelling the genetic origin of rare diseases. In clinical practice, serum Mg2+ should be determined in calcium and PTH-related disorders. |
| doi_str_mv | 10.1371/journal.pone.0239965 |
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The Cystathionine-β-synthase (CBS)-pair domain divalent metal cation transport mediators (CNNMs) have been described to be involved in maintaining Mg2+ homeostasis. Among these CNNMs, CNNM2 is expressed in the basolateral membrane of the kidney tubules where it is involved in Mg2+ reabsorption. A total of four patients, two of them with a suspected disorder of calcium metabolism, and two patients with a clinical diagnosis of primary tubulopathy were screened for mutations by Next-Generation Sequencing (NGS). We found one novel likely pathogenic variant in the heterozygous state (c.2384C>A; p.(Ser795*)) in the CNNM2 gene in a family with a suspected disorder of calcium metabolism. In this family, hypomagnesemia was indirectly discovered. Moreover, we observed three novel variants of uncertain significance in heterozygous state in the other three patients (c.557G>C; p.(Ser186Thr), c.778A>T; p.(Ile260Phe), and c.1003G>A; p.(Asp335Asn)). Our study shows the utility of Next-Generation Sequencing in unravelling the genetic origin of rare diseases. In clinical practice, serum Mg2+ should be determined in calcium and PTH-related disorders.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0239965</identifier><identifier>PMID: 32997713</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adenosine triphosphate ; Adolescent ; Adult ; Amino acids ; Binding sites ; Biology and Life Sciences ; Calcium ; Calcium metabolism ; Cation Transport Proteins - chemistry ; Cation Transport Proteins - genetics ; Codon, Nonsense ; Deoxyribonucleic acid ; DNA ; Endocrinology ; Female ; Genes ; Genetic aspects ; Genetic variation ; Genomes ; Health aspects ; Heterozygote ; High-Throughput Nucleotide Sequencing ; Homeostasis ; Hospitals ; Humans ; Hypomagnesemia ; Infant ; Intellectual disabilities ; Laboratories ; Magnesium ; Magnesium - blood ; Magnesium deficiency ; Male ; Medical research ; Medicine and Health Sciences ; Membrane proteins ; Metabolism ; Metal ions ; Mutation ; Nephrology ; Next-generation sequencing ; Parathyroid hormone ; Patients ; Pediatrics ; Physical Sciences ; Physiological aspects ; Polymorphism, Single Nucleotide ; Proteins ; Rare diseases ; Reabsorption ; Renal Tubular Transport, Inborn Errors - diagnosis ; Renal Tubular Transport, Inborn Errors - genetics ; Research and analysis methods ; Sequence Analysis, DNA ; Software ; Tubules</subject><ispartof>PloS one, 2020-09, Vol.15 (9), p.e0239965-e0239965</ispartof><rights>COPYRIGHT 2020 Public Library of Science</rights><rights>2020 García-Castaño et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2020 García-Castaño et al 2020 García-Castaño et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5005-1891a810dc8b9da968a92d8852e77ffc2f817aac961cda9d29a29074a79ddea53</citedby><cites>FETCH-LOGICAL-c5005-1891a810dc8b9da968a92d8852e77ffc2f817aac961cda9d29a29074a79ddea53</cites><orcidid>0000-0002-4032-9842 ; 0000-0002-9734-6600 ; 0000-0001-6189-8211 ; 0000-0003-3650-2785</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527205/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527205/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79569,79570</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32997713$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>García-Castaño, Alejandro</creatorcontrib><creatorcontrib>Madariaga, Leire</creatorcontrib><creatorcontrib>Antón-Gamero, Montserrat</creatorcontrib><creatorcontrib>Mejia, Natalia</creatorcontrib><creatorcontrib>Ponce, Jenny</creatorcontrib><creatorcontrib>Gómez-Conde, Sara</creatorcontrib><creatorcontrib>Pérez de Nanclares, Gustavo</creatorcontrib><creatorcontrib>De la Hoz, Ana Belén</creatorcontrib><creatorcontrib>Martínez, Rosa</creatorcontrib><creatorcontrib>Saso, Laura</creatorcontrib><creatorcontrib>Martínez de LaPiscina, Idoia</creatorcontrib><creatorcontrib>Urrutia, Inés</creatorcontrib><creatorcontrib>Velasco, Olaia</creatorcontrib><creatorcontrib>Aguayo, Aníbal</creatorcontrib><creatorcontrib>Castaño, Luis</creatorcontrib><creatorcontrib>Gaztambide, Sonia</creatorcontrib><title>Novel variant in the CNNM2 gene associated with dominant hypomagnesemia</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>The maintenance of magnesium (Mg2+) homeostasis is essential for human life. The Cystathionine-β-synthase (CBS)-pair domain divalent metal cation transport mediators (CNNMs) have been described to be involved in maintaining Mg2+ homeostasis. Among these CNNMs, CNNM2 is expressed in the basolateral membrane of the kidney tubules where it is involved in Mg2+ reabsorption. A total of four patients, two of them with a suspected disorder of calcium metabolism, and two patients with a clinical diagnosis of primary tubulopathy were screened for mutations by Next-Generation Sequencing (NGS). We found one novel likely pathogenic variant in the heterozygous state (c.2384C>A; p.(Ser795*)) in the CNNM2 gene in a family with a suspected disorder of calcium metabolism. In this family, hypomagnesemia was indirectly discovered. Moreover, we observed three novel variants of uncertain significance in heterozygous state in the other three patients (c.557G>C; p.(Ser186Thr), c.778A>T; p.(Ile260Phe), and c.1003G>A; p.(Asp335Asn)). Our study shows the utility of Next-Generation Sequencing in unravelling the genetic origin of rare diseases. In clinical practice, serum Mg2+ should be determined in calcium and PTH-related disorders.</description><subject>Adenosine triphosphate</subject><subject>Adolescent</subject><subject>Adult</subject><subject>Amino acids</subject><subject>Binding sites</subject><subject>Biology and Life Sciences</subject><subject>Calcium</subject><subject>Calcium metabolism</subject><subject>Cation Transport Proteins - chemistry</subject><subject>Cation Transport Proteins - genetics</subject><subject>Codon, Nonsense</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>Endocrinology</subject><subject>Female</subject><subject>Genes</subject><subject>Genetic aspects</subject><subject>Genetic variation</subject><subject>Genomes</subject><subject>Health aspects</subject><subject>Heterozygote</subject><subject>High-Throughput Nucleotide Sequencing</subject><subject>Homeostasis</subject><subject>Hospitals</subject><subject>Humans</subject><subject>Hypomagnesemia</subject><subject>Infant</subject><subject>Intellectual disabilities</subject><subject>Laboratories</subject><subject>Magnesium</subject><subject>Magnesium - blood</subject><subject>Magnesium deficiency</subject><subject>Male</subject><subject>Medical research</subject><subject>Medicine and Health Sciences</subject><subject>Membrane proteins</subject><subject>Metabolism</subject><subject>Metal ions</subject><subject>Mutation</subject><subject>Nephrology</subject><subject>Next-generation sequencing</subject><subject>Parathyroid hormone</subject><subject>Patients</subject><subject>Pediatrics</subject><subject>Physical Sciences</subject><subject>Physiological aspects</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Proteins</subject><subject>Rare diseases</subject><subject>Reabsorption</subject><subject>Renal Tubular Transport, Inborn Errors - 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Science Collection</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>García-Castaño, Alejandro</au><au>Madariaga, Leire</au><au>Antón-Gamero, Montserrat</au><au>Mejia, Natalia</au><au>Ponce, Jenny</au><au>Gómez-Conde, Sara</au><au>Pérez de Nanclares, Gustavo</au><au>De la Hoz, Ana Belén</au><au>Martínez, Rosa</au><au>Saso, Laura</au><au>Martínez de LaPiscina, Idoia</au><au>Urrutia, Inés</au><au>Velasco, Olaia</au><au>Aguayo, Aníbal</au><au>Castaño, Luis</au><au>Gaztambide, Sonia</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Novel variant in the CNNM2 gene associated with dominant hypomagnesemia</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2020-09-30</date><risdate>2020</risdate><volume>15</volume><issue>9</issue><spage>e0239965</spage><epage>e0239965</epage><pages>e0239965-e0239965</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>The maintenance of magnesium (Mg2+) homeostasis is essential for human life. The Cystathionine-β-synthase (CBS)-pair domain divalent metal cation transport mediators (CNNMs) have been described to be involved in maintaining Mg2+ homeostasis. Among these CNNMs, CNNM2 is expressed in the basolateral membrane of the kidney tubules where it is involved in Mg2+ reabsorption. A total of four patients, two of them with a suspected disorder of calcium metabolism, and two patients with a clinical diagnosis of primary tubulopathy were screened for mutations by Next-Generation Sequencing (NGS). We found one novel likely pathogenic variant in the heterozygous state (c.2384C>A; p.(Ser795*)) in the CNNM2 gene in a family with a suspected disorder of calcium metabolism. In this family, hypomagnesemia was indirectly discovered. Moreover, we observed three novel variants of uncertain significance in heterozygous state in the other three patients (c.557G>C; p.(Ser186Thr), c.778A>T; p.(Ile260Phe), and c.1003G>A; p.(Asp335Asn)). Our study shows the utility of Next-Generation Sequencing in unravelling the genetic origin of rare diseases. In clinical practice, serum Mg2+ should be determined in calcium and PTH-related disorders.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>32997713</pmid><doi>10.1371/journal.pone.0239965</doi><orcidid>https://orcid.org/0000-0002-4032-9842</orcidid><orcidid>https://orcid.org/0000-0002-9734-6600</orcidid><orcidid>https://orcid.org/0000-0001-6189-8211</orcidid><orcidid>https://orcid.org/0000-0003-3650-2785</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2020-09, Vol.15 (9), p.e0239965-e0239965 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_2447526752 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Adenosine triphosphate Adolescent Adult Amino acids Binding sites Biology and Life Sciences Calcium Calcium metabolism Cation Transport Proteins - chemistry Cation Transport Proteins - genetics Codon, Nonsense Deoxyribonucleic acid DNA Endocrinology Female Genes Genetic aspects Genetic variation Genomes Health aspects Heterozygote High-Throughput Nucleotide Sequencing Homeostasis Hospitals Humans Hypomagnesemia Infant Intellectual disabilities Laboratories Magnesium Magnesium - blood Magnesium deficiency Male Medical research Medicine and Health Sciences Membrane proteins Metabolism Metal ions Mutation Nephrology Next-generation sequencing Parathyroid hormone Patients Pediatrics Physical Sciences Physiological aspects Polymorphism, Single Nucleotide Proteins Rare diseases Reabsorption Renal Tubular Transport, Inborn Errors - diagnosis Renal Tubular Transport, Inborn Errors - genetics Research and analysis methods Sequence Analysis, DNA Software Tubules |
| title | Novel variant in the CNNM2 gene associated with dominant hypomagnesemia |
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