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

• Published in: PLoS genetics Vol. 14; no. 8; p. e1007602
• Main Authors: Ta-Shma, Asaf, Hjeij, Rim, Perles, Zeev, Dougherty, Gerard W, Abu Zahira, Ibrahim, Letteboer, Stef J F, Antony, Dinu, Darwish, Alaa, Mans, Dorus A, Spittler, Sabrina, Edelbusch, Christine, Cindrić, Sandra, Nöthe-Menchen, Tabea, Olbrich, Heike, Stuhlmann, Friederike, Aprea, Isabella, Pennekamp, Petra, Loges, Niki T, Breuer, Oded, Shaag, Avraham, Rein, Azaria J J T, Gulec, Elif Yilmaz, Gezdirici, Alper, Abitbul, Revital, Elias, Nael, Amirav, Israel, Schmidts, Miriam, Roepman, Ronald, Elpeleg, Orly, Omran, Heymut
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 27.08.2018; Public Library of Science (PLoS)
• Subjects: Adolescent; Adult; Animals; Axonemal Dyneins - genetics; Axonemal Dyneins - metabolism; Axoneme - metabolism; Axonemes; Biology and Life Sciences; Cardiology; Child; Child, Preschool; Cilia; Cilia - ultrastructure; Codon, Nonsense; Defects; Dynein; Embryos; Epithelial cells; Exome sequencing; Female; Flagella; Functional Laterality - genetics; Funding; Gene Expression Regulation; Gene mutation; Genetic aspects; Genetic Linkage; Genetic research; Health sciences; Homozygosity; Homozygote; Hospitals; Humans; Hydrocephalus; Immunofluorescence; Immunoprecipitation; Infant; Infertility; Infertility, Male - genetics; Inversion; Life sciences; Linkage analysis; Male; Male infertility; Medicine; Medicine and Health Sciences; Mice; Mice, Knockout; Middle Aged; Mutation; Nonsense mutation; Nuclear Proteins - deficiency; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Pediatrics; Pedigree; Polymorphism, Single Nucleotide; Proteins; Research and Analysis Methods; Respiratory system; Signal transduction; Situs inversus; Sperm Tail; Supervision; Whole Exome Sequencing; Young Adult; Istanbul Turkey; Netherlands; Turkey; Israel; Jerusalem Israel; Tel Aviv Israel; Germany
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1007602

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.