CNNM2 Mutations Cause Impaired Brain Development and Seizures in Patients with Hypomagnesemia
Publication Date
April 03, 2014
Journal
PLOS Genetics
Authors
Francisco J. Arjona, Jeroen H. F. De Baaij, Karl P. Schlingmann, Anke L. L. Lameris, et al
Volume
10
Issue
4
Pages
e1004267
DOI
https://dx.plos.org/10.1371/journal.pgen.1004267
Publisher URL
http://journals.plos.org/plosgenetics/article?id=10.1371%2Fjournal.pgen.1004267
PubMed
http://www.ncbi.nlm.nih.gov/pubmed/24699222
PubMed Central
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3974678
Europe PMC
http://europepmc.org/abstract/MED/24699222
Web of Science
000335499600011
Scopus
84901325411
Mendeley
http://www.mendeley.com/research/cnnm2-mutations-cause-impaired-brain-development-seizures-patients-hypomagnesemia
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Mendeley | Further Information

{"title"=>"CNNM2 Mutations Cause Impaired Brain Development and Seizures in Patients with Hypomagnesemia", "type"=>"journal", "authors"=>[{"first_name"=>"Francisco J.", "last_name"=>"Arjona", "scopus_author_id"=>"9943577200"}, {"first_name"=>"Jeroen H.F.", "last_name"=>"de Baaij", "scopus_author_id"=>"55192953600"}, {"first_name"=>"Karl P.", "last_name"=>"Schlingmann", "scopus_author_id"=>"8573263400"}, {"first_name"=>"Anke L.L.", "last_name"=>"Lameris", "scopus_author_id"=>"24399534200"}, {"first_name"=>"Erwin", "last_name"=>"van Wijk", "scopus_author_id"=>"6701437316"}, {"first_name"=>"Gert", "last_name"=>"Flik", "scopus_author_id"=>"7004588474"}, {"first_name"=>"Sabrina", "last_name"=>"Regele", "scopus_author_id"=>"56178481300"}, {"first_name"=>"G. Christoph", "last_name"=>"Korenke", "scopus_author_id"=>"8884859400"}, {"first_name"=>"Birgit", "last_name"=>"Neophytou", "scopus_author_id"=>"15127956200"}, {"first_name"=>"Stephan", "last_name"=>"Rust", "scopus_author_id"=>"7007055489"}, {"first_name"=>"Nadine", "last_name"=>"Reintjes", "scopus_author_id"=>"55303798200"}, {"first_name"=>"Martin", "last_name"=>"Konrad", "scopus_author_id"=>"7005482405"}, {"first_name"=>"René J.M.", "last_name"=>"Bindels", "scopus_author_id"=>"7006377933"}, {"first_name"=>"Joost G.J.", "last_name"=>"Hoenderop", "scopus_author_id"=>"7003635675"}], "year"=>2014, "source"=>"PLoS Genetics", "identifiers"=>{"sgr"=>"84901325411", "doi"=>"10.1371/journal.pgen.1004267", "isbn"=>"1553-7404 (Electronic)\\r1553-7390 (Linking)", "pmid"=>"24699222", "issn"=>"15537404", "scopus"=>"2-s2.0-84901325411", "pui"=>"373162860"}, "id"=>"9bde975e-e57d-334d-9384-eb62e6d1d25a", "abstract"=>"Intellectual disability and seizures are frequently associated with hypomagnesemia and have an important genetic component. However, to find the genetic origin of intellectual disability and seizures often remains challenging because of considerable genetic heterogeneity and clinical variability. In this study, we have identified new mutations in CNNM2 in five families suffering from mental retardation, seizures, and hypomagnesemia. For the first time, a recessive mode of inheritance of CNNM2 mutations was observed. Importantly, patients with recessive CNNM2 mutations suffer from brain malformations and severe intellectual disability. Additionally, three patients with moderate mental disability were shown to carry de novo heterozygous missense mutations in the CNNM2 gene. To elucidate the physiological role of CNNM2 and explain the pathomechanisms of disease, we studied CNNM2 function combining in vitro activity assays and the zebrafish knockdown model system. Using stable Mg(2+) isotopes, we demonstrated that CNNM2 increases cellular Mg2+ uptake in HEK293 cells and that this process occurs through regulation of the Mg(2+)-permeable cation channel TRPM7. In contrast, cells expressing mutated CNNM2 proteins did not show increased Mg(2+) uptake. Knockdown of cnnm2 isoforms in zebrafish resulted in disturbed brain development including neurodevelopmental impairments such as increased embryonic spontaneous contractions and weak touch-evoked escape behaviour, and reduced body Mg content, indicative of impaired renal Mg(2+) absorption. These phenotypes were rescued by injection of mammalian wild-type Cnnm2 cRNA, whereas mammalian mutant Cnnm2 cRNA did not improve the zebrafish knockdown phenotypes. We therefore concluded that CNNM2 is fundamental for brain development, neurological functioning and Mg(2+) homeostasis. By establishing the loss-of-function zebrafish model for CNNM2 genetic disease, we provide a unique system for testing therapeutic drugs targeting CNNM2 and for monitoring their effects on the brain and kidney phenotype.", "link"=>"http://www.mendeley.com/research/cnnm2-mutations-cause-impaired-brain-development-seizures-patients-hypomagnesemia", "reader_count"=>32, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>2, "Librarian"=>1, "Student > Doctoral Student"=>1, "Researcher"=>8, "Student > Ph. D. Student"=>2, "Other"=>5, "Student > Master"=>7, "Student > Bachelor"=>2, "Lecturer > Senior Lecturer"=>1, "Professor"=>3}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>2, "Librarian"=>1, "Student > Doctoral Student"=>1, "Researcher"=>8, "Student > Ph. D. Student"=>2, "Other"=>5, "Student > Master"=>7, "Student > Bachelor"=>2, "Lecturer > Senior Lecturer"=>1, "Professor"=>3}, "reader_count_by_subject_area"=>{"Biochemistry, Genetics and Molecular Biology"=>6, "Agricultural and Biological Sciences"=>14, "Medicine and Dentistry"=>5, "Pharmacology, Toxicology and Pharmaceutical Science"=>2, "Veterinary Science and Veterinary Medicine"=>1, "Psychology"=>1, "Social Sciences"=>2, "Immunology and Microbiology"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>5}, "Social Sciences"=>{"Social Sciences"=>2}, "Psychology"=>{"Psychology"=>1}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>14}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>6}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>2}, "Veterinary Science and Veterinary Medicine"=>{"Veterinary Science and Veterinary Medicine"=>1}}, "reader_count_by_country"=>{"Netherlands"=>1, "Mexico"=>1}, "group_count"=>3}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1448280"], "description"=>"<p>(A) Pedigrees of families F1–F5. Filled symbols represent affected individuals, mutant alleles are indicated by a minus (−) and plus (+) sign, respectively. (B) Localization of the mutations in the CNNM2 protein structure (Uniprot Q9H8M5). CNNM2 contains a long signal peptide (64 amino acids) that is cleaved at the membrane of the endoplasmic reticulum. The remaining part of the CNNM2 protein is trafficked to the plasma membrane, where it becomes functionally active. White dots show the locations of the mutations. (C–D) MRI of the brain of patient F1.1 (C, T2 weighed images) and patient F2.1 (D, T2 weighed images). Left: Coronal images demonstrating a defect in myelinization of U-fibers (arrows) in patient F1.1 in contrast to a normal myelin pattern in patient F2.1. Center: Coronal T2 weighted images showing widened outer cerebrospinal liquor spaces (dashed arrows) and lack of opercularization (solid arrows) in patient F1.1, whereas a regular brain volume and insular lobe is observed in patient F2.1. Right: Absence of cerebellar structural abnormalities in patients F1.1 and F2.1 on axial T2 weighted images at the level of the trigeminal nerve.</p>", "links"=>[], "tags"=>["Nephrology", "Mineral metabolism and the kidney", "neurology", "Developmental and pediatric neurology", "epilepsy", "resonance", "imaging", "studies"], "article_id"=>985805, "categories"=>["Biological Sciences"], "users"=>["Francisco J. Arjona", "Jeroen H. F. de Baaij", "Karl P. Schlingmann", "Anke L. L. Lameris", "Erwin Van Wijk", "Gert Flik", "Sabrina Regele", "G. Christoph Korenke", "Birgit Neophytou", "Stephan Rust", "Nadine Reintjes", "Martin Konrad", "René J. M. Bindels", "Joost G. J. Hoenderop"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1004267.g001", "stats"=>{"downloads"=>1, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Pedigrees_and_magnetic_resonance_imaging_MRI_studies_of_families_with_primary_hypomagnesemia_/985805", "title"=>"Pedigrees and magnetic resonance imaging (MRI) studies of families with primary hypomagnesemia.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-04-03 03:01:33"}
  • {"files"=>["https://ndownloader.figshare.com/files/1448294"], "description"=>"<p>Clinical and biochemical data of patients.</p>", "links"=>[], "tags"=>["Nephrology", "Mineral metabolism and the kidney", "neurology", "Developmental and pediatric neurology", "epilepsy", "biochemical"], "article_id"=>985819, "categories"=>["Biological Sciences"], "users"=>["Francisco J. Arjona", "Jeroen H. F. de Baaij", "Karl P. Schlingmann", "Anke L. L. Lameris", "Erwin Van Wijk", "Gert Flik", "Sabrina Regele", "G. Christoph Korenke", "Birgit Neophytou", "Stephan Rust", "Nadine Reintjes", "Martin Konrad", "René J. M. Bindels", "Joost G. J. Hoenderop"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1004267.t001", "stats"=>{"downloads"=>3, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Clinical_and_biochemical_data_of_patients_/985819", "title"=>"Clinical and biochemical data of patients.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-04-03 03:01:33"}
  • {"files"=>["https://ndownloader.figshare.com/files/1448293"], "description"=>"<p>(A) Phenotypes in zebrafish embryos untreated (wild-type) or following treatment with <i>cnnm2b</i>-MO (8 ng MO/embryo) or control-MO. See <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004267#pgen-1004267-g006\" target=\"_blank\">Figure 6</a> for an explanation of the abbreviations shown. (B) Distribution of phenotypes and (C) Mg content (n = 10 per experimental condition) in zebrafish embryos untreated (wild-type) or injected with 8 ng of <i>cnnm2b</i>-MO or control-MO and exposed to a medium with a concentration of Mg<sup>2+</sup> of 0.33 or 25 mM. Numbers on top of the bars indicate the number of animals in each experimental condition. (D) Restoration of normal brain development by co-injection of <i>cnnm2b</i>-MO (8 ng MO/embryo) with cRNA encoding for wild-type (WT) CNNM2 (50 pg cRNA/embryo), and not by co-injection with cRNA encoding for mutant (MT, p.Glu357Lys) CNNM2 (50 pg cRNA/embryo). (E) Spontaneous contractions in zebrafish embryos untreated (wild-type) or injected with 8 ng of <i>cnnm2b</i>-MO or control-MO and exposed to a medium with a concentration of Mg<sup>2+</sup> of 0.33 or 25 mM (n = 30 per experimental condition). (F) Restoration of normal spontaneous contraction activity (n = 30 per experimental condition) by co-injection of <i>cnnm2b</i>-MO (8 ng MO/embryo) with cRNA encoding for wild-type (WT) CNNM2 (50 pg cRNA/embryo), and not by co-injection with cRNA encoding for mutant (MT, p.Glu357Lys) CNNM2 (50 pg cRNA/embryo). Data are presented as mean ± SEM. *<i>P</i><0.05 <i>versus</i> wild-type and control. <sup>#</sup><i>P</i><0.05 <i>versus</i> Mg<sup>2+</sup>-normal (0.33 Mm Mg<sup>2+</sup>) medium. Data are presented as mean ± SEM. Different letters indicate significant differences between mean values in experimental groups (<i>P</i><0.05).</p>", "links"=>[], "tags"=>["Nephrology", "Mineral metabolism and the kidney", "neurology", "Developmental and pediatric neurology", "epilepsy", "causes", "abnormalities", "spontaneous", "contractions", "zebrafish", "embryos"], "article_id"=>985818, "categories"=>["Biological Sciences"], "users"=>["Francisco J. Arjona", "Jeroen H. F. de Baaij", "Karl P. Schlingmann", "Anke L. L. Lameris", "Erwin Van Wijk", "Gert Flik", "Sabrina Regele", "G. Christoph Korenke", "Birgit Neophytou", "Stephan Rust", "Nadine Reintjes", "Martin Konrad", "René J. M. Bindels", "Joost G. J. Hoenderop"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1004267.g007", "stats"=>{"downloads"=>2, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Dysfunctional_c_nnm2b_causes_brain_abnormalities_and_increased_spontaneous_contractions_in_zebrafish_embryos_25_hpf_/985818", "title"=>"Dysfunctional c<i>nnm2b</i> causes brain abnormalities and increased spontaneous contractions in zebrafish embryos (25 hpf).", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-04-03 03:01:33"}
  • {"files"=>["https://ndownloader.figshare.com/files/1448334", "https://ndownloader.figshare.com/files/1448335", "https://ndownloader.figshare.com/files/1448336", "https://ndownloader.figshare.com/files/1448337", "https://ndownloader.figshare.com/files/1448338", "https://ndownloader.figshare.com/files/1448339", "https://ndownloader.figshare.com/files/1448340", "https://ndownloader.figshare.com/files/1448341", "https://ndownloader.figshare.com/files/1448342"], "description"=>"<div><p>Intellectual disability and seizures are frequently associated with hypomagnesemia and have an important genetic component. However, to find the genetic origin of intellectual disability and seizures often remains challenging because of considerable genetic heterogeneity and clinical variability. In this study, we have identified new mutations in <i>CNNM2</i> in five families suffering from mental retardation, seizures, and hypomagnesemia. For the first time, a recessive mode of inheritance of <i>CNNM2</i> mutations was observed. Importantly, patients with recessive <i>CNNM2</i> mutations suffer from brain malformations and severe intellectual disability. Additionally, three patients with moderate mental disability were shown to carry <i>de novo</i> heterozygous missense mutations in the <i>CNNM2</i> gene. To elucidate the physiological role of CNNM2 and explain the pathomechanisms of disease, we studied CNNM2 function combining <i>in vitro</i> activity assays and the zebrafish knockdown model system. Using stable Mg<sup>2+</sup> isotopes, we demonstrated that CNNM2 increases cellular Mg<sup>2+</sup> uptake in HEK293 cells and that this process occurs through regulation of the Mg<sup>2+</sup>-permeable cation channel TRPM7. In contrast, cells expressing mutated CNNM2 proteins did not show increased Mg<sup>2+</sup> uptake. Knockdown of <i>cnnm2</i> isoforms in zebrafish resulted in disturbed brain development including neurodevelopmental impairments such as increased embryonic spontaneous contractions and weak touch-evoked escape behaviour, and reduced body Mg content, indicative of impaired renal Mg<sup>2+</sup> absorption. These phenotypes were rescued by injection of mammalian wild-type <i>Cnnm2</i> cRNA, whereas mammalian mutant <i>Cnnm2</i> cRNA did not improve the zebrafish knockdown phenotypes. We therefore concluded that CNNM2 is fundamental for brain development, neurological functioning and Mg<sup>2+</sup> homeostasis. By establishing the loss-of-function zebrafish model for CNNM2 genetic disease, we provide a unique system for testing therapeutic drugs targeting CNNM2 and for monitoring their effects on the brain and kidney phenotype.</p></div>", "links"=>[], "tags"=>["Nephrology", "Mineral metabolism and the kidney", "neurology", "Developmental and pediatric neurology", "epilepsy", "mutations", "impaired", "seizures", "patients"], "article_id"=>985859, "categories"=>["Biological Sciences"], "users"=>["Francisco J. Arjona", "Jeroen H. F. de Baaij", "Karl P. Schlingmann", "Anke L. L. Lameris", "Erwin Van Wijk", "Gert Flik", "Sabrina Regele", "G. Christoph Korenke", "Birgit Neophytou", "Stephan Rust", "Nadine Reintjes", "Martin Konrad", "René J. M. Bindels", "Joost G. J. Hoenderop"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1004267.s001", "https://dx.doi.org/10.1371/journal.pgen.1004267.s002", "https://dx.doi.org/10.1371/journal.pgen.1004267.s003", "https://dx.doi.org/10.1371/journal.pgen.1004267.s004", "https://dx.doi.org/10.1371/journal.pgen.1004267.s005", "https://dx.doi.org/10.1371/journal.pgen.1004267.s006", "https://dx.doi.org/10.1371/journal.pgen.1004267.s007", "https://dx.doi.org/10.1371/journal.pgen.1004267.s008", "https://dx.doi.org/10.1371/journal.pgen.1004267.s009"], "stats"=>{"downloads"=>18, "page_views"=>29, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_CNNM2_Mutations_Cause_Impaired_Brain_Development_and_Seizures_in_Patients_with_Hypomagnesemia_/985859", "title"=>"CNNM2 Mutations Cause Impaired Brain Development and Seizures in Patients with Hypomagnesemia", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2014-04-03 03:01:33"}
  • {"files"=>["https://ndownloader.figshare.com/files/1448284"], "description"=>"<p>(A) Time curve of <sup>25</sup>Mg<sup>2+</sup> uptake in mock, wild-type CNNM2 and mutant CNNM2 transfected cells. Symbols indicate cells transfected with the vector empty (• mock) or containing <i>Cnnm2</i> sequences encoding for wild-type or mutant CNNM2 proteins (▪ CNNM2, ▴ CNNM2-p.Glu122Lys, ▾ CNNM2-p.Ser269Trp, ⧫ CNNM2-p.Leu330Phe, ○ CNNM2-p.Glu357Lys, □ CNNM2-p.Thr568Ile). Each data point represent the mean of 3 independent experiments ± SEM. * indicates significant differences compared to mock (<i>P</i><0.05). (B) Representative immunoblots showing that p.Glu122Lys and p.Ser269Trp mutations reduce CNNM2 membrane expression (upper blot) and a CNNM2 expression control (lower blot). Quantification of cell surface expression of wild-type (WT) and mutant CNNM2 proteins corrected for total protein expression. Results are the mean ± SEM of 3 independent experiments. * indicate significant differences compared to WT CNNM2 transfected cells (<i>P</i><0.05).</p>", "links"=>[], "tags"=>["Nephrology", "Mineral metabolism and the kidney", "neurology", "Developmental and pediatric neurology", "epilepsy", "mutations", "impair", "uptake", "hek293"], "article_id"=>985809, "categories"=>["Biological Sciences"], "users"=>["Francisco J. Arjona", "Jeroen H. F. de Baaij", "Karl P. Schlingmann", "Anke L. L. Lameris", "Erwin Van Wijk", "Gert Flik", "Sabrina Regele", "G. Christoph Korenke", "Birgit Neophytou", "Stephan Rust", "Nadine Reintjes", "Martin Konrad", "René J. M. Bindels", "Joost G. J. Hoenderop"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1004267.g003", "stats"=>{"downloads"=>2, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_CNNM2_mutations_impair_Mg_2_uptake_in_HEK293_cells_/985809", "title"=>"CNNM2 mutations impair Mg<sup>2+</sup> uptake in HEK293 cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-04-03 03:01:33"}
  • {"files"=>["https://ndownloader.figshare.com/files/1448281"], "description"=>"<p>(A) Time curve of <sup>25</sup>Mg<sup>2+</sup> uptake in mock (circles) and CNNM2 (squares) transfected cells. (B) Representation of the normalized Mg<sup>2+</sup> uptake after 5 minutes. (C) <sup>25</sup>Mg<sup>2+</sup> uptake in the presence of inhibitors of ion transporters, black bars represent mock cells and white bars represent CNNM2-transfected cells. (D) Dose-response curve of <sup>25</sup>Mg<sup>2+</sup> transport inhibition by 2-APB in mock (circles) and CNNM2 (squares) transfected cells. (E) The effect of Na<sup>+</sup> and Cl<sup>−</sup> availability on <sup>25</sup>Mg<sup>2+</sup> uptake in mock (black bars) and CNNM2 (white bars) transfected cells. (F) <sup>25</sup>Mg<sup>2+</sup> uptake as a function of extracellular <sup>25</sup>Mg<sup>2+</sup> availability in mock (circles) and CNNM2 (squares) transfected cells. (G) <sup>25</sup>Mg<sup>2+</sup> extrusion in mock (circles) and CNNM2 (squares) transfected cells. Each data point represent the mean of 3 independent experiments ± SEM. * indicates significant differences compared to mock (<i>P</i><0.05).</p>", "links"=>[], "tags"=>["Nephrology", "Mineral metabolism and the kidney", "neurology", "Developmental and pediatric neurology", "epilepsy", "uptake", "hek293"], "article_id"=>985806, "categories"=>["Biological Sciences"], "users"=>["Francisco J. Arjona", "Jeroen H. F. de Baaij", "Karl P. Schlingmann", "Anke L. L. Lameris", "Erwin Van Wijk", "Gert Flik", "Sabrina Regele", "G. Christoph Korenke", "Birgit Neophytou", "Stephan Rust", "Nadine Reintjes", "Martin Konrad", "René J. M. Bindels", "Joost G. J. Hoenderop"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1004267.g002", "stats"=>{"downloads"=>1, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_CNNM2_increases_Mg_2_uptake_in_HEK293_cells_/985806", "title"=>"CNNM2 increases Mg<sup>2+</sup> uptake in HEK293 cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-04-03 03:01:33"}
  • {"files"=>["https://ndownloader.figshare.com/files/1448292"], "description"=>"<p>(A) Phenotypes in zebrafish embryos untreated (wild-type) or following treatment with <i>cnnm2a</i>-MO (2 ng MO/embryo) or control-MO. Abbreviations indicate the following parts in the zebrafish embryonic brain: M, midbrain; T, tectum; MHB, midbrain-hindbrain boundary; FV, fourth ventricle; and H, hindbrain. (B) Distribution of phenotypes and (C) Mg content (n = 10 per experimental condition) in zebrafish embryos untreated (wild-type) or injected with 2 ng of <i>cnnm2a</i>-MO or control-MO and exposed to a medium with a concentration of Mg<sup>2+</sup> of 0.33 or 25 mM. Numbers on top of the bars indicate the number of animals in each experimental condition. (D) Restoration of normal brain development by co-injection of <i>cnnm2a</i>-MO (2 ng MO/embryo) with cRNA encoding for wild-type (WT) CNNM2 (50 pg cRNA/embryo), and not by co-injection with cRNA encoding for mutant (MT, p.Glu357Lys) CNNM2 (50 pg cRNA/embryo). (E) Spontaneous contractions in zebrafish embryos untreated (wild-type) or injected with 2 ng of <i>cnnm2a</i>-MO or control-MO and exposed to a medium with a concentration of Mg<sup>2+</sup> of 0.33 or 25 mM (n = 30 per experimental condition). (F) Restoration of normal spontaneous contraction activity (n = 30 per experimental condition) by co-injection of <i>cnnm2a</i>-MO (2 ng MO/embryo) with cRNA encoding for wild-type (WT) CNNM2 (50 pg cRNA/embryo), and not by co-injection with cRNA encoding for mutant (MT, p.Glu357Lys) CNNM2 (50 pg cRNA/embryo). Data are presented as mean ± SEM. *<i>P</i><0.05 <i>versus</i> wild-type and control. <sup>#</sup><i>P</i><0.05 <i>versus</i> Mg<sup>2+</sup>-normal (0.33 mM Mg<sup>2+</sup>) medium. Data are presented as mean ± SEM. Different letters indicate significant differences between mean values in experimental groups (<i>P</i><0.05).</p>", "links"=>[], "tags"=>["Nephrology", "Mineral metabolism and the kidney", "neurology", "Developmental and pediatric neurology", "epilepsy", "causes", "abnormalities", "spontaneous", "contractions", "zebrafish", "embryos"], "article_id"=>985817, "categories"=>["Biological Sciences"], "users"=>["Francisco J. Arjona", "Jeroen H. F. de Baaij", "Karl P. Schlingmann", "Anke L. L. Lameris", "Erwin Van Wijk", "Gert Flik", "Sabrina Regele", "G. Christoph Korenke", "Birgit Neophytou", "Stephan Rust", "Nadine Reintjes", "Martin Konrad", "René J. M. Bindels", "Joost G. J. Hoenderop"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1004267.g006", "stats"=>{"downloads"=>3, "page_views"=>23, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Dysfunctional_c_nnm2a_causes_brain_abnormalities_and_increased_spontaneous_contractions_in_zebrafish_embryos_25_hpf_/985817", "title"=>"Dysfunctional c<i>nnm2a</i> causes brain abnormalities and increased spontaneous contractions in zebrafish embryos (25 hpf).", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-04-03 03:01:33"}
  • {"files"=>["https://ndownloader.figshare.com/files/1448290"], "description"=>"<p>(A) mRNA expression of <i>cnnm2a</i> in developing zebrafish. Expression patterns were analysed by RT-qPCR (n = 6 per time point). (B) Survival curve at 5 dpf (n = 3 per experimental condition). The dose of zero represents injection with control-MO. (C) Morphological phenotypes in zebrafish larvae (5 dpf) in <i>cnnm2a</i> knockdown experiments. (D) Distribution of morphological phenotypes in zebrafish larvae (5 dpf) untreated (wild-type) or injected with different doses of <i>cnnm2a</i>-MO or control-MO. Numbers on top of the bars indicate the number of animals in each experimental condition. (E) Distribution of morphological phenotypes in zebrafish larvae at 5 dpf in rescue experiments. The wild-type phenotype (class I) was restored in morphants by co-injection of <i>cnnm2a</i>-MO (2 ng MO/embryo) with wild-type (WT) CNNM2 cRNA (50 pg cRNA/embryo), but not with mutant (MT, p.Glu357Lys) CNNM2 cRNA (50 pg cRNA/embryo). (F) Magnesium content in zebrafish injected with different doses of <i>cnnm2a</i>-MO, the dose of zero represents injection with control-MO (n = 10 per experimental condition except in 8 ng MO-injected zebrafish where n = 5). (G) Rescue of Mg wasting in morphant zebrafish by co-injection of <i>cnnm2a</i>-MO (2 ng MO/embryo) with cRNA encoding for wild-type (WT) CNNM2 (50 pg cRNA/embryo). Co-injection with cRNA encoding for mutant (MT, p.Glu357Lys) CNNM2 (50 pg cRNA/embryo) did not restore Mg levels (n = 10 per experimental condition). Data are presented as mean ± SEM. Different letters indicate significant differences between mean values in experimental groups (<i>P</i><0.05).</p>", "links"=>[], "tags"=>["Nephrology", "Mineral metabolism and the kidney", "neurology", "Developmental and pediatric neurology", "epilepsy", "mg", "wasting", "zebrafish", "larvae"], "article_id"=>985815, "categories"=>["Biological Sciences"], "users"=>["Francisco J. Arjona", "Jeroen H. F. de Baaij", "Karl P. Schlingmann", "Anke L. L. Lameris", "Erwin Van Wijk", "Gert Flik", "Sabrina Regele", "G. Christoph Korenke", "Birgit Neophytou", "Stephan Rust", "Nadine Reintjes", "Martin Konrad", "René J. M. Bindels", "Joost G. J. Hoenderop"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1004267.g004", "stats"=>{"downloads"=>5, "page_views"=>57, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Knockdown_of_cnnm2a_results_in_Mg_wasting_in_zebrafish_larvae_5_dpf_/985815", "title"=>"Knockdown of <i>cnnm2a</i> results in Mg wasting in zebrafish larvae (5 dpf).", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-04-03 03:01:33"}
  • {"files"=>["https://ndownloader.figshare.com/files/1448291"], "description"=>"<p>(A) mRNA expression of <i>cnnm2b</i> in developing zebrafish. Expression patterns were analysed by RT-qPCR (n = 6 per time point). (B) Survival curve at 5 dpf (n = 3 per experimental condition). The dose of zero represents injection with control-MO. (C) Morphological phenotypes in zebrafish larvae (5 dpf) in <i>cnnm2b</i> knockdown experiments. (D) Distribution of morphological phenotypes in zebrafish larvae (5 dpf) untreated (wild-type) or injected with different doses of <i>cnnm2b</i>-MO or control-MO. Brain malformations (widened cerebrospinal fluid spaces, class IV phenotype) are prominent in morphants injected with 4–8 ng MO/embryo. Numbers on top of the bars indicate the number of animals in each experimental condition. (E) Distribution of morphological phenotypes in zebrafish larvae at 5 dpf in rescue experiments. The wild-type phenotype (class I) was restored in morphants by co-injection of <i>cnnm2b</i>-MO (8 ng MO/embryo) with wild-type (WT) CNNM2 cRNA (50 pg cRNA/embryo), but not with mutant (MT, p.Glu357Lys) CNNM2 cRNA (50 pg cRNA/embryo). (F) Magnesium content in zebrafish injected with different doses of <i>cnnm2b</i>-MO. The dose of zero represents injection with control-MO (n = 10 per experimental condition). (G) Rescue of Mg wasting in morphant zebrafish by co-injection of <i>cnnm2b</i>-MO (8 ng MO/embryo) with cRNA encoding for wild-type (WT) CNNM2 (50 pg cRNA/embryo). Co-injection with cRNA encoding for mutant (MT, p.Glu357Lys) CNNM2 (50 pg cRNA/embryo) did not restore Mg levels (n = 10 per experimental condition). Data are presented as mean ± SEM. Different letters indicate significant differences between mean values in experimental groups (<i>P</i><0.05).</p>", "links"=>[], "tags"=>["Nephrology", "Mineral metabolism and the kidney", "neurology", "Developmental and pediatric neurology", "epilepsy", "mg", "wasting", "malformations", "zebrafish", "larvae"], "article_id"=>985816, "categories"=>["Biological Sciences"], "users"=>["Francisco J. Arjona", "Jeroen H. F. de Baaij", "Karl P. Schlingmann", "Anke L. L. Lameris", "Erwin Van Wijk", "Gert Flik", "Sabrina Regele", "G. Christoph Korenke", "Birgit Neophytou", "Stephan Rust", "Nadine Reintjes", "Martin Konrad", "René J. M. Bindels", "Joost G. J. Hoenderop"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1004267.g005", "stats"=>{"downloads"=>2, "page_views"=>19, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Knockdown_of_cnnm2b_results_in_Mg_wasting_and_brain_malformations_in_zebrafish_larvae_5_dpf_/985816", "title"=>"Knockdown of <i>cnnm2b</i> results in Mg wasting and brain malformations in zebrafish larvae (5 dpf).", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-04-03 03:01:33"}

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Relative Metric

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