• PMID: 30148830
• Gene Name: MNS1
• Condition: Male infertility
• Association: Associated
• Mutation: p.Arg242*, p.Gln203*
• Sex: Male
• Infertility type: Male infertility

Homozygous loss-of-function mutations in MNS1 cause laterality defects and likely male infertility

Ta-Shma A, Hjeij R, Perles Z, Dougherty GW, Abu Zahira I, Letteboer SJF, Antony D, Darwish A, Mans DA, Spittler S, Edelbusch C, Cindri? S, Nöthe-Menchen T, Olbrich H, Stuhlmann F, Aprea I, Pennekamp P, Loges NT, Breuer O, Shaag A, Rein AJJT, Gulec EY, Gezdirici A, Abitbul R, Elias N, Amirav I, Schmidts M, Roepman R, Elpeleg O, Omran H.

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. FAU - Ta-Shma, Asaf AU - Ta-Shma A AUID- ORCID: 0000-0003-0076-9568 AD - Department of Pediatric Cardiology, Hadassah, Hebrew University Medical Center, Jerusalem, Israel. AD - Monique and Jacques Roboh Department of Genetic Research, Hadassah, Hebrew University Medical Center, Jerusalem, Israel. FAU - Hjeij, Rim AU - Hjeij R AD - Department of General Pediatrics, University Hospital Muenster, Muenster, Germany. FAU - Perles, Zeev AU - Perles Z AD - Department of Pediatric Cardiology, Hadassah, Hebrew University Medical Center, Jerusalem, Israel. FAU - Dougherty, Gerard W AU - Dougherty GW AD - Department of General Pediatrics, University Hospital Muenster, Muenster, Germany. FAU - Abu Zahira, Ibrahim AU - Abu Zahira I AD - Department of Pediatric Cardiology, Hadassah, Hebrew University Medical Center, Jerusalem, Israel. FAU - Letteboer, Stef J F AU - Letteboer SJF AD - Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands. AD - Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, the Netherlands. FAU - Antony, Dinu AU - Antony D AD - Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands. AD - Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, the Netherlands. AD - Pediatric Genetics Division, Center for Pediatrics and Adolescent Medicine, Faculty of Medicine, Freiburg University, Freiburg, Germany. FAU - Darwish, Alaa AU - Darwish A AD - Department of Pediatric Cardiology, Hadassah, Hebrew University Medical Center, Jerusalem, Israel. FAU - Mans, Dorus A AU - Mans DA AD - Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands. AD - Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, the Netherlands. FAU - Spittler, Sabrina AU - Spittler S AD - Department of General Pediatrics, University Hospital Muenster, Muenster, Germany. FAU - Edelbusch, Christine AU - Edelbusch C AD - Department of General Pediatrics, University Hospital Muenster, Muenster, Germany. FAU - Cindrić, Sandra AU - Cindrić S AUID- ORCID: 0000-0002-8303-100X AD - Department of General Pediatrics, University Hospital Muenster, Muenster, Germany. FAU - Nöthe-Menchen, Tabea AU - Nöthe-Menchen T AD - Department of General Pediatrics, University Hospital Muenster, Muenster, Germany. FAU - Olbrich, Heike AU - Olbrich H AD - Department of General Pediatrics, University Hospital Muenster, Muenster, Germany. FAU - Stuhlmann, Friederike AU - Stuhlmann F AD - Department of General Pediatrics, University Hospital Muenster, Muenster, Germany. FAU - Aprea, Isabella AU - Aprea I AD - Department of General Pediatrics, University Hospital Muenster, Muenster, Germany. FAU - Pennekamp, Petra AU - Pennekamp P AD - Department of General Pediatrics, University Hospital Muenster, Muenster, Germany. FAU - Loges, Niki T AU - Loges NT AD - Department of General Pediatrics, University Hospital Muenster, Muenster, Germany. FAU - Breuer, Oded AU - Breuer O AD - Pediatric Pulmonology Unit, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. FAU - Shaag, Avraham AU - Shaag A AD - Monique and Jacques Roboh Department of Genetic Research, Hadassah, Hebrew University Medical Center, Jerusalem, Israel. FAU - Rein, Azaria J J T AU - Rein AJJT AD - Department of Pediatric Cardiology, Hadassah, Hebrew University Medical Center, Jerusalem, Israel. FAU - Gulec, Elif Yilmaz AU - Gulec EY AD - University of Health Sciences, Kanuni Sultan Suleyman, Training and Research Hospital, Department of Medical Genetics, Istanbul, Turkey. FAU - Gezdirici, Alper AU - Gezdirici A AD - University of Health Sciences, Kanuni Sultan Suleyman, Training and Research Hospital, Department of Medical Genetics, Istanbul, Turkey. FAU - Abitbul, Revital AU - Abitbul R AD - Pediatric Department, Ziv Medical Center, Faculty of Medicine, Bar Ilan University, Safed, Israel. FAU - Elias, Nael AU - Elias N AD - Saint Vincent Hospital, Nazareth, Faculty of Medicine, Bar Ilan University, Israel. FAU - Amirav, Israel AU - Amirav I AUID- ORCID: 0000-0002-6917-5285 AD - Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada. AD - Pediatric Pulmonology Unit, Tel Aviv Medical Center, Tel Aviv, Israel. FAU - Schmidts, Miriam AU - Schmidts M AD - Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands. AD - Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, the Netherlands. AD - Pediatric Genetics Division, Center for Pediatrics and Adolescent Medicine, Faculty of Medicine, Freiburg University, Freiburg, Germany. FAU - Roepman, Ronald AU - Roepman R AD - Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands. AD - Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, the Netherlands. FAU - Elpeleg, Orly AU - Elpeleg O AD - Monique and Jacques Roboh Department of Genetic Research, Hadassah, Hebrew University Medical Center, Jerusalem, Israel.