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

• DOI: 10.1371/journal.pgen.1007602
• Publication Date: 2018-08-27T22:21:06Z
• Authors: Asaf Ta-Shma; Rim Hjeij; Zeev Perles; Gerard W. Dougherty; Ibrahim Abu Zahira; Stef J. F. Letteboer; Dinu Antony; Alaa Darwish; Dorus A. Mans; Sabrina Spittler; Christine Edelbusch; Sandra Cindrić; Tabea Nöthe-Menchen; Heike Olbrich; Friederike Stuhlmann; Isabella Aprea; Petra Pennekamp; Niki T. Loges; Oded Breuer; Avraham Shaag; Azaria J. J. T. Rein; Elif Yilmaz Gulec; Alper Gezdirici; Revital Abitbul; Nael Elias; Israel Amirav; Miriam Schmidts; Ronald Roepman; Orly Elpeleg; Heymut Omran
• Keywords: Nonsense mutation; Compound heterozygosity; Ciliopathies; Motile cilium; Intraflagellar Transport

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 whole exome sequencing, we identified two recessive loss-of-function MNS1 mutations five individuals from four consanguineous families: 1) a homozygous nonsense mutation p.Arg242* males with 2) p.Gln203* one female recurrent infections additionally carrying DNAH5. Consistent observed these individuals, found Mns1 to be expressed mouse embryonic ventral node. Immunofluorescence further revealed that localizes axonemes as well sperm flagella human. In-depth ultrastructural analyses confirmed subtle outer dynein arm (ODA) defect epithelial cells resembling findings reported Mns1-deficient mice. Ultrastructural combined DNAH5 indicated role for process ODA docking (ODA-DC) distal axonemes. Furthermore, co-immunoprecipitation yeast hybrid demonstrated dimerizes interacts complex component CCDC114. Overall, demonstrate deficiency humans causes (situs inversus) likely male plays ODA-DC assembly.