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.
| Original language | English |
|---|---|
| Article number | e1007602 |
| Journal | PLoS Genetics |
| Volume | 14 |
| Issue number | 8 |
| DOIs | |
| State | Published - Aug 2018 |
| Externally published | Yes |
Bibliographical note
Publisher Copyright:© 2018 Ta-Shma et al. http://creativecommons.org/licenses/by/4.0/.
Funding
This work was supported by the “Deutsche Forschungsgemeinschaft” (DFG HJ 7/1-1 to RH; DFG OM 6/4, OM 6/7, OM 6/8, OM 6/10 and DFG KFO 326/OM6/11 to HO; OL450/1 to H. Olbrich) and the Interdisziplinaeres Zentrum für Klinische Forschung Muenster IZKF (Om2/009/12, Om2/015/16) to HO, EU 7th FP under GA nr. 262055 [ESGI], as a Transnational Access project of the European Sequencing and Genotyping Infrastructure, BESTCILIA, GA nr. 305404 to HO; the Schroeder Stiftung, Kindness for Kids, Care for Rare Foundation and Eva Luise und Horst Köhler Stiftung to HO. This work was supported by the Trudy Mandel Louis Charitable Trust to OE and by the Chief Scientist Office of the Ministry of Health, Israel (grant no. 3–6176) to IA. MS acknowledges funding from Radboudumc and RIMLS Nijmegen (Hypatia tenure track fellowship), the “Deutsche Forschungsgemeinschaft” (DFG CRC1140 KIDGEM) and the European research Council (ERC StG TREATCilia, grant No 716344). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We thank the PCD-affected individuals and their families for their participation and acknowledge the German patient support group ‘Kartagener Syndrom und Primaere Ciliaere Dyskinesie e.V.’. We thank D. Ernst, M. Herting, L. Schwiddessen, A. Robbers, K. Wohlgemuth, A. Dorißen, C. Westermann and F.J. Seesing for excellent technical work. We also thank Dr. Cansaran Tanidir and Dr. Alper Guzeltas for the diagnosis and referral of the individual MS-II-1 for genetic workup. We also would like to thank the Genome Aggregation Database (gnomAD) and the groups that provided exome and genome variant data to this resource. A full list of contributing groups can be found at http://gnomad.broadinstitute.org/about.
| Funders | Funder number |
|---|---|
| Seventh Framework Programme | 716344 |
| FP7 Ideas: European Research Council | 262055, 305404 |
| European Commission | |
| Deutsche Forschungsgemeinschaft | OM 6/4, KFO 326, HJ 7/1-1, OL450/1, OM 6/8, OM 6/7, CRC1140 KIGDEM |
| Radboud Universitair Medisch Centrum | |
| Office of the Chief Scientist, Ministry of Health | 3-6176 |
