title: Overexpression of RPGR leads to male infertility in mice due to defects in flagellar assembly.
abstract: Male infertility is one possible consequence of a group of disorders arising from dysfunction of cilia. Ciliopathies include primary ciliary dyskinesia, polycystic kidney disease, Usher syndrome, nephronophthisis, Bardet-Biedl syndrome, Alstrom syndrome, and Meckel-Gruber syndrome as well as some forms of retinal degenerations. Mutations in the retinitis pigmentosa GTPase regulator gene (RPGR) are best known for leading to retinal degeneration but have also been associated with ciliary dysfunctions affecting other tissues. To further study the involvement of RPGR in ciliopathies, transgenic mouse lines overexpressing RPGR were generated. Animals carrying the transgene in varying copy numbers were investigated. We found that infertility due to aberrant spermatozoa correlated with increased copy numbers. In animals with moderately increased gene copies of Rpgr, structural disorganization in the flagellar midpiece, outer dense fibers, and fibrous sheath was apparent. In contrast, in animals with high copy numbers, condensed sperm heads were present, but the flagellum was absent in the vast majority of spermatozoa, although early steps of flagellar biogenesis were observed. This complexity of defects in flagellar assembly suggests a role of RPGR in intraflagellar transport processes.
authors.affiliation: Division of Medical Molecular Genetics and Gene Diagnostics, Institute for Medical Genetics, University of Zurich, 8603 Schwerzenbach, Switzerland.
authors.forename: Sandra
authors.initials: S
authors.lastname: Brunner
authors.forename: Dvora
authors.initials: D
authors.lastname: Colman
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Travis
authors.forename: Ulrich F O
authors.initials: UF
authors.lastname: Luhmann
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
authors.forename: Silke
authors.initials: S
authors.lastname: Feil
authors.forename: Coni
authors.initials: C
authors.lastname: Imsand
authors.forename: Jacquelyn
authors.initials: J
authors.lastname: Nelson
authors.forename: Christian
authors.initials: C
authors.lastname: Grimm
authors.forename: Thomas
authors.initials: T
authors.lastname: Rülicke
authors.forename: Reinald
authors.initials: R
authors.lastname: Fundele
authors.forename: John
authors.initials: J
authors.lastname: Neidhardt
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Berger
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D005136:Eye Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D018628:Gene Dosage / Q000502:physiology; D007248:Infertility, Male / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D013082:Sperm Tail / Q000378:metabolism* / Q000502:physiology / Q000648:ultrastructure; D013091:Spermatogenesis / Q000235:genetics*; D013094:Spermatozoa / Q000002:abnormalities*; D013737:Testis / Q000166:cytology; D015854:Up-Regulation / Q000502:physiology
chemical_list: D002352:Carrier Proteins; D005136:Eye Proteins; C513598:RPGR protein, mouse