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Overexpression of RPGR Leads to Male Infertility in Mice Due to Defects in Flagellar Assembly¹

Division of Medical Molecular Genetics and Gene Diagnostics,³ Institute for Medical Genetics, University of Zurich, 8603 Schwerzenbach, Switzerland Baker Institute for Animal Health,⁴ College of Veterinary Medicine, Cornell University, Ithaca, New York 14853 Division of Molecular Therapy,⁶ UCL Institute of Ophthalmology, EC1V 9EL London, United Kingdom Department of Development and Genetics,⁵ Uppsala University, 75236 Uppsala, Sweden Laboratory for Retinal Cell Biology,⁷ Department of Ophthalmology, University of Zurich, 8001 Zurich, Switzerland Institute of Laboratory Animal Science and Biomodels Austria,⁸ University of Veterinary Medicine Vienna, 1210 Vienna, Austria

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.

flagellum, infertility, sperm, spermatogenesis, testis

¹Supported by the Swiss National Science Foundation, grant number 3100-067786 (to W.B.).

Correspondence: ²Wolfgang Berger, Division of Medical Molecular Genetics and Gene Diagnostics, Institute of Medical Genetics, University of Zurich, Schorenstrasse 16, 8603 Schwerzenbach, Switzerland. FAX: 41 44 655 72 13; e-mail: berger{at}medgen.uzh.ch