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Homozygous mutation of AURKC yields large-headed polyploid spermatozoa and causes male infertility


The World Health Organization conservatively estimates that 80 million people suffer from infertility worldwide. Male factors are believed to be responsible for 20–50% of all infertility cases, but microdeletions of the Y chromosome are the only genetic defects altering human spermatogenesis that have been reported repeatedly1. We focused our work on infertile men with a normal somatic karyotype but typical spermatozoa mainly characterized by large heads, a variable number of tails and an increased chromosomal content (OMIM 243060)2,3,4. We performed a genome-wide microsatellite scan on ten infertile men presenting this characteristic phenotype. In all of these men, we identified a common region of homozygosity harboring the aurora kinase C gene (AURKC) with a single nucleotide deletion in the AURKC coding sequence. In addition, we show that this founder mutation results in premature termination of translation, yielding a truncated protein that lacks the kinase domain. We conclude that the absence of AURKC causes male infertility owing to the production of large-headed multiflagellar polyploid spermatozoa.

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Figure 1: Large-headed spermatozoa.
Figure 2: Segregation of the AURKC deletion in family R6.
Figure 3: L49W fsx22 leads to premature termination of translation.
Figure 4: Proportion of the different chromosomal constitutions detected by FISH for chromosomes X,Y and 18 on a total of 3,689 spermatozoa from subjects G1, G2, G3, R1 and R3.

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We thank all affected individuals and family members for their participation. We thank E. Panetto of Applied Imaging for his help with the fluorescent microscopy and O. Amina for technical help. We thank S. Dutertre and C. Prigent (Rennes University) for sending us the AURKC wild-type clone. We thank S. Kimmins for discussion about their knockout animals. We are also grateful to P. Richard (la Pitié Salpétrière, Paris) for providing control DNAs. R.S.R. and T.O. are supported by a grant from the Agence Nationale de la Recherche (ANR). This work was supported in part by the Fondation d'Aide à la Recherche Organon (FARO) and the Direction de la Recherche Clinique (DRC) du CHU de Grenoble.

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Correspondence to Pierre F Ray.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Genotypes of 14 men with large-headed spermatozoa. (PDF 38 kb)

Supplementary Table 1

Sequences of Aurora Kinase C primers. (PDF 48 kb)

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Dieterich, K., Soto Rifo, R., Faure, A. et al. Homozygous mutation of AURKC yields large-headed polyploid spermatozoa and causes male infertility. Nat Genet 39, 661–665 (2007).

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