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A Heterozygous Mutation Disrupting the SPAG16 Gene Results in Biochemical Instability of Central Apparatus Components of the Human Sperm Axoneme¹

Department of Obstetrics & Gynecology,³ Virginia Commonwealth University, Richmond, Virginia 23298 Pulmonary and Critical Care Medicine,⁴ University of North Carolina, Chapel Hill, North Carolina 27599 Department of Obstetrics & Gynecology,⁵ and Pulmonary and Critical Care,⁶ University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205 Laboratorio de Andrología,⁷ Unidad de Reproducción Humana, Clínica Tambre, 28002 Madrid, Spain INSERM U. 428, Faculte de Medecine,⁸ Universite Paris-Descartes, 75006 Paris, France INSERM U. 654, Hôpital Henri-Mondor,⁹ 94010 Créteil cedex, France Center for Research on Reproduction and Women's Health,¹⁰ University of Pennsylvania, Philadelphia, Pennsylvania 19104

ABSTRACT

The SPAG16 gene encodes two major transcripts, one for the 71-kDa SPAG16L, which is the orthologue of the Chlamydomonas rheinhardtii central apparatus protein PF20, and a smaller transcript, which codes for the 35-kDa SPAG16S nuclear protein that represents the C-terminus (exons 11–16) of SPAG16L. We have previously reported that a targeted mutation in exon 11 of the Spag16 gene impairs spermatogenesis and prevents transmission of the mutant allele in chimeric mice. In the present report, we describe a heterozygous mutation in exon 13 of the SPAG16 gene, which causes a frame shift and premature stop codon, affording the opportunity to compare mutations with similar impacts on SPAG16L and SPAG16S for male reproductive function in mice and men. We studied two male heterozygotes for the SPAG16 mutation, both of which were fertile. Freezing-boiling of isolated sperm from both affected males resulted in the loss of the SPAG16L protein, SPAG6, another central apparatus protein that interacts with SPAG16L, and the 28-kDa fragment of SPAG17, which associates with SPAG6. These proteins were also lost after freezing-boiling cycles of sperm extracts from mice that were heterozygous for an inactivating mutation (exons 2 and 3) in Spag16. Our findings suggest that a heterozygous mutation that affects both SPAG16L and SPAG16S does not cause male infertility in man, but is associated with reduced stability of the interacting proteins of the central apparatus in response to a thermal challenge, a phenotype shared by the sperm of mice heterozygous for a mutation that affects SPAG16L.

axoneme, central apparatus, mutation, sperm motility, SPAG16,, Spag16L

¹Supported by National Institutes of Health Grants HD37416, HD06724, and U54 RR019480.

Correspondence: ²Zhibing Zhang, Department of Obstetrics & Gynecology, Virginia Commonwealth University, 1101 East Marshall Street, Room 11-028A, Richmond, VA 23298. FAX: 804 828 0573; e-mail: zzhang4{at}vcu.edu