2. Academic Validation
  3. Homozygous loss-of-function mutations in MNS1 cause laterality defects and likely male infertility

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

  • PLoS Genet. 2018 Aug 27;14(8):e1007602. doi: 10.1371/journal.pgen.1007602.
Asaf Ta-Shma 1 2,  Rim Hjeij 3,  Zeev Perles 1,  Gerard W Dougherty 3,  Ibrahim Abu Zahira 1,  Stef J F Letteboer 4 5,  Dinu Antony 4 5 6,  Alaa Darwish 1,  Dorus A Mans 4 5,  Sabrina Spittler 3,  Christine Edelbusch 3,  Sandra Cindrić 3,  Tabea Nöthe-Menchen 3,  Heike Olbrich 3,  Friederike Stuhlmann 3,  Isabella Aprea 3,  Petra Pennekamp 3,  Niki T Loges 3,  Oded Breuer 7,  Avraham Shaag 2,  Azaria J J T Rein 1,  Elif Yilmaz Gulec 8,  Alper Gezdirici 8,  Revital Abitbul 9,  Nael Elias 10,  Israel Amirav 11 12,  Miriam Schmidts 4 5 6,  Ronald Roepman 4 5,  Orly Elpeleg 2,  Heymut Omran 3
Affiliations

Affiliations

  • 1 Department of Pediatric Cardiology, Hadassah, Hebrew University Medical Center, Jerusalem, Israel.
  • 2 Monique and Jacques Roboh Department of Genetic Research, Hadassah, Hebrew University Medical Center, Jerusalem, Israel.
  • 3 Department of General Pediatrics, University Hospital Muenster, Muenster, Germany.
  • 4 Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
  • 5 Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, the Netherlands.
  • 6 Pediatric Genetics Division, Center for Pediatrics and Adolescent Medicine, Faculty of Medicine, Freiburg University, Freiburg, Germany.
  • 7 Pediatric Pulmonology Unit, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
  • 8 University of Health Sciences, Kanuni Sultan Suleyman, Training and Research Hospital, Department of Medical Genetics, Istanbul, Turkey.
  • 9 Pediatric Department, Ziv Medical Center, Faculty of Medicine, Bar Ilan University, Safed, Israel.
  • 10 Saint Vincent Hospital, Nazareth, Faculty of Medicine, Bar Ilan University, Israel.
  • 11 Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada.
  • 12 Pediatric Pulmonology Unit, Tel Aviv Medical Center, Tel Aviv, Israel.
PMID: 30148830 DOI: 10.1371/journal.pgen.1007602
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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