Homozygous loss-of-function mutations in MNS1 cause laterality defects and likely male infertility
The clinical spectrum of ciliopathies affecting motile cilia spans impaired mucociliary clearance in the respiratory system, laterality defects including heart malformations, infertility and hydrocephalus. Using linkage analysis and whole exome sequencing, we identified two recessive loss-of-functio...
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| Published in | PLoS genetics Vol. 14; no. 8; p. e1007602 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
Public Library of Science
27.08.2018
Public Library of Science (PLoS) |
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| Abstract | The clinical spectrum of ciliopathies affecting motile cilia spans impaired mucociliary clearance in the respiratory system, laterality defects including heart malformations, infertility and hydrocephalus. Using linkage analysis and whole exome sequencing, we identified two recessive loss-of-function MNS1 mutations in five individuals from four consanguineous families: 1) a homozygous nonsense mutation p.Arg242* in four males with laterality defects and infertility and 2) a homozygous nonsense mutation p.Gln203* in one female with laterality defects and recurrent respiratory infections additionally carrying homozygous mutations in DNAH5. Consistent with the laterality defects observed in these individuals, we found Mns1 to be expressed in mouse embryonic ventral node. Immunofluorescence analysis further revealed that MNS1 localizes to the axonemes of respiratory cilia as well as sperm flagella in human. In-depth ultrastructural analyses confirmed a subtle outer dynein arm (ODA) defect in the axonemes of respiratory epithelial cells resembling findings reported in Mns1-deficient mice. Ultrastructural analyses in the female carrying combined mutations in MNS1 and DNAH5 indicated a role for MNS1 in the process of ODA docking (ODA-DC) in the distal respiratory axonemes. Furthermore, co-immunoprecipitation and yeast two hybrid analyses demonstrated that MNS1 dimerizes and interacts with the ODA docking complex component CCDC114. Overall, we demonstrate that MNS1 deficiency in humans causes laterality defects (situs inversus) and likely male infertility and that MNS1 plays a role in the ODA-DC assembly. |
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| AbstractList | The clinical spectrum of ciliopathies affecting motile cilia spans impaired mucociliary clearance in the respiratory system, laterality defects including heart malformations, infertility and hydrocephalus. Using linkage analysis and whole exome sequencing, we identified two recessive loss-of-function MNS1 mutations in five individuals from four consanguineous families: 1) a homozygous nonsense mutation p.Arg242* in four males with laterality defects and infertility and 2) a homozygous nonsense mutation p.Gln203* in one female with laterality defects and recurrent respiratory infections additionally carrying homozygous mutations in DNAH5. Consistent with the laterality defects observed in these individuals, we found Mns1 to be expressed in mouse embryonic ventral node. Immunofluorescence analysis further revealed that MNS1 localizes to the axonemes of respiratory cilia as well as sperm flagella in human. In-depth ultrastructural analyses confirmed a subtle outer dynein arm (ODA) defect in the axonemes of respiratory epithelial cells resembling findings reported in Mns1-deficient mice. Ultrastructural analyses in the female carrying combined mutations in MNS1 and DNAH5 indicated a role for MNS1 in the process of ODA docking (ODA-DC) in the distal respiratory axonemes. Furthermore, co-immunoprecipitation and yeast two hybrid analyses demonstrated that MNS1 dimerizes and interacts with the ODA docking complex component CCDC114. Overall, we demonstrate that MNS1 deficiency in humans causes laterality defects (situs inversus) and likely male infertility and that MNS1 plays a role in the ODA-DC assembly. The clinical spectrum of ciliopathies affecting motile cilia spans impaired mucociliary clearance in the respiratory system, laterality defects including heart malformations, infertility and hydrocephalus. Using linkage analysis and whole exome sequencing, we identified two recessive loss-of-function MNS1 mutations in five individuals from four consanguineous families: 1) a homozygous nonsense mutation p.Arg242* in four males with laterality defects and infertility and 2) a homozygous nonsense mutation p.Gln203* in one female with laterality defects and recurrent respiratory infections additionally carrying homozygous mutations in DNAH5 . Consistent with the laterality defects observed in these individuals, we found Mns1 to be expressed in mouse embryonic ventral node. Immunofluorescence analysis further revealed that MNS1 localizes to the axonemes of respiratory cilia as well as sperm flagella in human. In-depth ultrastructural analyses confirmed a subtle outer dynein arm (ODA) defect in the axonemes of respiratory epithelial cells resembling findings reported in Mns1 -deficient mice. Ultrastructural analyses in the female carrying combined mutations in MNS1 and DNAH5 indicated a role for MNS1 in the process of ODA docking (ODA-DC) in the distal respiratory axonemes. Furthermore, co-immunoprecipitation and yeast two hybrid analyses demonstrated that MNS1 dimerizes and interacts with the ODA docking complex component CCDC114. Overall, we demonstrate that MNS1 deficiency in humans causes laterality defects ( situs inversus ) and likely male infertility and that MNS1 plays a role in the ODA-DC assembly. Although no clear explanation is yet provided for the correct establishment of the left-right body asymmetry in human, animal studies have clearly shown that tiny-hair-like organelles in the ventral node of the embryo—called motile nodal monocilia—beat regularly and play an important role in this process. To date, different genetic variants were identified to cause laterality defects but the list is still incomplete. Here, we describe two loss-of-function variants in MNS1 in individuals suffering from laterality defects and infertility. This finding is particularly important because laterality defects can also be associated with increased risk of congenital heart disease. By examining a specific case with loss-of-function variants in MNS1 and DNAH5 (the latter encodes for DNAH5, a main component of the motor protein complexes providing the ciliary beating), we show that MNS1 plays a role in stabilizing structures in the motile cilium that helps the attachment of motor proteins–such as DNAH5- to the microtubules to ensure a correct beating of the cilia. Further studies of the function of MNS1 may implicate new biological pathways affecting susceptibility to laterality defects and infertility. The clinical spectrum of ciliopathies affecting motile cilia spans impaired mucociliary clearance in the respiratory system, laterality defects including heart malformations, infertility and hydrocephalus. Using linkage analysis and whole exome sequencing, we identified two recessive loss-of-function MNS1 mutations in five individuals from four consanguineous families: 1) a homozygous nonsense mutation p.Arg242* in four males with laterality defects and infertility and 2) a homozygous nonsense mutation p.Gln203* in one female with laterality defects and recurrent respiratory infections additionally carrying homozygous mutations in DNAH5. Consistent with the laterality defects observed in these individuals, we found Mns1 to be expressed in mouse embryonic ventral node. Immunofluorescence analysis further revealed that MNS1 localizes to the axonemes of respiratory cilia as well as sperm flagella in human. In-depth ultrastructural analyses confirmed a subtle outer dynein arm (ODA) defect in the axonemes of respiratory epithelial cells resembling findings reported in Mns1-deficient mice. Ultrastructural analyses in the female carrying combined mutations in MNS1 and DNAH5 indicated a role for MNS1 in the process of ODA docking (ODA-DC) in the distal respiratory axonemes. Furthermore, co-immunoprecipitation and yeast two hybrid analyses demonstrated that MNS1 dimerizes and interacts with the ODA docking complex component CCDC114. Overall, we demonstrate that MNS1 deficiency in humans causes laterality defects (situs inversus) and likely male infertility and that MNS1 plays a role in the ODA-DC assembly.The clinical spectrum of ciliopathies affecting motile cilia spans impaired mucociliary clearance in the respiratory system, laterality defects including heart malformations, infertility and hydrocephalus. Using linkage analysis and whole exome sequencing, we identified two recessive loss-of-function MNS1 mutations in five individuals from four consanguineous families: 1) a homozygous nonsense mutation p.Arg242* in four males with laterality defects and infertility and 2) a homozygous nonsense mutation p.Gln203* in one female with laterality defects and recurrent respiratory infections additionally carrying homozygous mutations in DNAH5. Consistent with the laterality defects observed in these individuals, we found Mns1 to be expressed in mouse embryonic ventral node. Immunofluorescence analysis further revealed that MNS1 localizes to the axonemes of respiratory cilia as well as sperm flagella in human. In-depth ultrastructural analyses confirmed a subtle outer dynein arm (ODA) defect in the axonemes of respiratory epithelial cells resembling findings reported in Mns1-deficient mice. Ultrastructural analyses in the female carrying combined mutations in MNS1 and DNAH5 indicated a role for MNS1 in the process of ODA docking (ODA-DC) in the distal respiratory axonemes. Furthermore, co-immunoprecipitation and yeast two hybrid analyses demonstrated that MNS1 dimerizes and interacts with the ODA docking complex component CCDC114. Overall, we demonstrate that MNS1 deficiency in humans causes laterality defects (situs inversus) and likely male infertility and that MNS1 plays a role in the ODA-DC assembly. |
| Audience | Academic |
| Author | Rein, Azaria J. J. T. Ta-Shma, Asaf Edelbusch, Christine Elpeleg, Orly Gulec, Elif Yilmaz Elias, Nael Dougherty, Gerard W. Pennekamp, Petra Mans, Dorus A. Nöthe-Menchen, Tabea Gezdirici, Alper Omran, Heymut Stuhlmann, Friederike Olbrich, Heike Aprea, Isabella Abu Zahira, Ibrahim Breuer, Oded Abitbul, Revital Darwish, Alaa Antony, Dinu Letteboer, Stef J. F. Spittler, Sabrina Loges, Niki T. Cindrić, Sandra Perles, Zeev Amirav, Israel Hjeij, Rim Shaag, Avraham Roepman, Ronald Schmidts, Miriam |
| AuthorAffiliation | 11 Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada 3 Department of General Pediatrics, University Hospital Muenster, Muenster, Germany 6 Pediatric Genetics Division, Center for Pediatrics and Adolescent Medicine, Faculty of Medicine, Freiburg University, Freiburg, Germany 2 Monique and Jacques Roboh Department of Genetic Research, Hadassah, Hebrew University Medical Center, Jerusalem, Israel 1 Department of Pediatric Cardiology, Hadassah, Hebrew University Medical Center, Jerusalem, Israel 4 Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands 9 Pediatric Department, Ziv Medical Center, Faculty of Medicine, Bar Ilan University, Safed, Israel 5 Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, the Netherlands 12 Pediatric Pulmonology Unit, Tel Aviv Medical Center, Tel Aviv, Israel 7 Pediatric Pulmonology Unit, Hadassah-Hebrew University Medical Center, Jerusalem, Israel 8 University of Health Scie |
| AuthorAffiliation_xml | – name: 2 Monique and Jacques Roboh Department of Genetic Research, Hadassah, Hebrew University Medical Center, Jerusalem, Israel – name: 7 Pediatric Pulmonology Unit, Hadassah-Hebrew University Medical Center, Jerusalem, Israel – name: 10 Saint Vincent Hospital, Nazareth, Faculty of Medicine, Bar Ilan University, Israel – name: 11 Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada – name: 1 Department of Pediatric Cardiology, Hadassah, Hebrew University Medical Center, Jerusalem, Israel – name: Monash University, AUSTRALIA – name: 9 Pediatric Department, Ziv Medical Center, Faculty of Medicine, Bar Ilan University, Safed, Israel – name: 12 Pediatric Pulmonology Unit, Tel Aviv Medical Center, Tel Aviv, Israel – name: 6 Pediatric Genetics Division, Center for Pediatrics and Adolescent Medicine, Faculty of Medicine, Freiburg University, Freiburg, Germany – name: 8 University of Health Sciences, Kanuni Sultan Suleyman, Training and Research Hospital, Department of Medical Genetics, Istanbul, Turkey – name: 4 Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands – name: 3 Department of General Pediatrics, University Hospital Muenster, Muenster, Germany – name: 5 Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, the Netherlands |
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| ContentType | Journal Article |
| Copyright | COPYRIGHT 2018 Public Library of Science 2018 Ta-Shma 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. 2018 Ta-Shma et al 2018 Ta-Shma et al |
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| DOI | 10.1371/journal.pgen.1007602 |
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| SubjectTerms | Axonemes Biology and Life Sciences Cardiology Cilia Defects Dynein Embryos Epithelial cells Exome sequencing Flagella Funding Gene mutation Genetic aspects Genetic research Health sciences Homozygosity Hospitals Hydrocephalus Immunofluorescence Immunoprecipitation Infertility Inversion Life sciences Linkage analysis Male infertility Medicine Medicine and Health Sciences Mutation Nonsense mutation Pediatrics Proteins Research and Analysis Methods Respiratory system Signal transduction Situs inversus Supervision |
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| Title | Homozygous loss-of-function mutations in MNS1 cause laterality defects and likely male infertility |
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