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Disruption of Spermatogenesis and Infertility in Ataxia with Oculomotor Apraxia Type 2 (AOA2)

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Abstract

Ataxia with oculomotor apraxia type 2 (AOA2) is a rare autosomal recessive cerebellar ataxia characterized by onset between 10 and 20 years of age and a range of neurological features that include progressive cerebellar atrophy, axonal sensorimotor neuropathy, oculomotor apraxia in a majority of patients, and elevated serum alpha-fetoprotein (AFP). AOA2 is caused by mutation of the SETX gene which encodes senataxin, a DNA/RNA helicase involved in transcription regulation, RNA processing, and DNA maintenance. Disruption of senataxin in rodents led to defective spermatogenesis and sterility in males uncovering a key role for senataxin in male germ cell survival. Here, we report the first clinical and cellular evidence of impaired spermatogenesis in AOA2 patients. We assessed sperm production in three AOA2 patients and testicular pathology in one patient and compared the findings to those of Setx-knockout mice. Sperm production was impaired in all patients assessed (3/3, 100%). Analyses of testicular biopsies from an AOA2 patient recapitulate features of the histology seen in Setx-knockout mice, strongly suggesting an underlying mechanism centering on DNA-damage-mediated germ cell apoptosis. These findings support a role for senataxin in human reproductive function and highlight a novel clinical feature of AOA2 that extends the extra-neurological roles of senataxin. This raises an important reproductive counseling issue for clinicians, and fertility specialists should be aware of SETX mutations as a possible diagnosis in young male patients presenting with oligospermia or azoospermia since infertility may presage the later onset of neurological manifestations in some individuals.

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Acknowledgements

The authors thank the patients and their families for their participation in this project. We thank John Luff and HMRC animal house staff for the maintenance of the mice and Dr. Abrey Yeo for assistance with the preparation of the figures.

Funding

This work was supported by the Australian Research Council (ARC, DP 130100389 to M.F.L.) and the National Institute for Neurological Disorders and Stroke (R01NS082094 to B.L.F.). BLF acknowledges support through donations to the University of California by the DeMint Family and the Ruehl Family.

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Authors and Affiliations

  1. Cancer and Neuroscience, UQ Centre for Clinical Research (UQCCR), The University of Queensland, Building 71/918, Royal Brisbane and Women’s Hospital Campus, Brisbane, QLD, 4029, Australia

    Olivier J. Becherel & Martin F. Lavin

  2. School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, QLD, 4072, Australia

    Olivier J. Becherel

  3. Departments of Neurology and Human Genetics, David Geffen School of Medicine, University of California Los Angeles (UCLA), 695 Charles E. Young Drive South, Gonda Room 1206, Los Angeles, CA, 90095, USA

    Brent L. Fogel

  4. Department of Urology, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, 90095, USA

    Scott I. Zeitlin

  5. Aquesta Uropathology and University of Queensland School of Medicine, Brisbane, QLD, 4029, Australia

    Hemamali Samaratunga

  6. Christopher Chen Oocyte Biology Laboratory, UQ Centre for Clinical Research (UQCCR), The University of Queensland, Royal Brisbane and Women’s Hospital Campus, Brisbane, QLD, 4029, Australia

    Jessica Greaney & Hayden Homer

Authors
  1. Olivier J. Becherel
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  2. Brent L. Fogel
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  4. Hemamali Samaratunga
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  5. Jessica Greaney
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  7. Martin F. Lavin
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Corresponding authors

Correspondence to Brent L. Fogel or Martin F. Lavin.

Ethics declarations

All animal work and experiments have been approved by The University of Queensland Animal Ethics Committee (HMRC/UQCCR/155/15/ARC). Written informed consent was obtained to collect biological samples from patients for further analysis. All study methods were approved by the Institutional Review Board of the University of California, Los Angeles (UCLA).

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The authors declare that they have no conflict of interest.

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Becherel, O.J., Fogel, B.L., Zeitlin, S.I. et al. Disruption of Spermatogenesis and Infertility in Ataxia with Oculomotor Apraxia Type 2 (AOA2). Cerebellum 18, 448–456 (2019). https://doi.org/10.1007/s12311-019-01012-w

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  • DOI: https://doi.org/10.1007/s12311-019-01012-w

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