Homozygous Loss-of-function Mutations in MNS1 Cause Laterality Defects and Likely Male Infertility

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 four individuals from three consanguineous families. Three males from two families suffering from infertility, laterality defects and severe congenital heart defects shared a homozygous nonsense mutation, p.Arg242*, and one female had a homozygous nonsense mutation p.Gln203* in MNS1. Immunofluorescence analysis revealed that MNS1 is an axonemal protein of respiratory cilia as well as sperm flagella. Ultrastructural analyses confirmed a subtle outer dynein arm (ODA) defect in the axonemes of respiratory epithelial cells resembling findings reported in Mns1-deficient mice. Co-immunoprecipitation and yeast two hybrid analyses demonstrate that MNS1 dimerizes and also interacts with the ODA docking complex component CCDC114. Overall, we demonstrate that MNS1 deficiency in humans causes prominent laterality and male fertility defects resembling findings reported in Mns1-deficient mice.