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Case Reports
. 2019 Jun;18(3):448-456.
doi: 10.1007/s12311-019-01012-w.

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

Olivier J Becherel  1   2 , Brent L Fogel  3 , Scott I Zeitlin  4 , Hemamali Samaratunga  5 , Jessica Greaney  6 , Hayden Homer  6 , Martin F Lavin  7
Affiliations
Case Reports

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

Olivier J Becherel et al. Cerebellum. 2019 Jun.

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.

Keywords: Cerebellum; Fertility; Gait disorders/ataxia; Genetics; Sperm.

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Conflict of interest statement

Conflict of interest: All the authors declare that there is no conflict of interest.

Figures

Figure 1.
Figure 1.. Spermatogenesis is disrupted in an AOA2 patient as shown by the absence of mature germ cells in seminiferous tubules.
Hematoxylin and eosin (H&E)-stained sections of testis from A. control and AOA2 patient sample, and B. adult Setx+/+ and Setx−/− mice. Black arrows indicate mature germ cells in the control and Setx+/+ while vacuolated seminiferous tubules in which both spermatozoa and mature spermatids are absent are observed in both AOA2 patient and Setx−/− seminiferous tubules. Scale bar, 20 μm.
Figure 2.
Figure 2.. Presence of germs cells in control, AOA2, and Setx mice seminiferous tubules.
A. Immunostaining of germ cells in human AOA2 and control testis biopsy sections, and B. mouse Setx+/+ and Setx−/− seminiferous tubules. Germ cells were stained for VASA (DDX4/MVH), an RNA binding protein with an RNA-dependent helicase that is essential for germ cell development. Nuclei were counterstained with DAPI. Scale bar, 20 μm.
Figure 3.
Figure 3.. Elevated levels of DNA damage in AOA2 patient germ cells compared to control.
Increased levels of DNA breaks are shown by immunostaining with anti-γH2AX (pSer139 H2AX) antibody were detected in AOA2 patient germ cells and Setx−/− seminiferous tubules as compared to Control and Setx+/+. Both low and high magnification images are shown with scale bars of 100μm and 20μm, respectively. Nuclei were stained with DAPI.
Figure 4.
Figure 4.. Detection of R-loops (DNA:RNA hybrid structures) in AOA2, control, Setx+/+ and Setx−/− testis.
A. Percentage of R-loop-positive tubules in Control, AOA2, Setx+/+ and Setx−/− samples. Tubules containing ≥ 1 R-loop-positive germ cell were scored as R-loop-positive tubule. B. Example of R-loop staining in control and AOA2 patient testis biopsy sections. C. R-loop staining in Setx+/+ and Setx−/− mouse testis seminiferous tubules. R-loops were detected in germ cells as shown by the white arrow. While many R-loop-positive germs cells were detected per tubule in Setx−/− mice as shown in (C), only one to two R-loop-positive germ cells were detected per tubule in the AOA2 patient sample (B).
Figure 5.
Figure 5.. Elevated levels of germ cells apoptosis in an AOA2 patient.
A. TUNEL-stained testis sections from control, AOA2 patient and adult Setx+/+ and Setx−/− mice. White arrow indicates TUNEL-positive germ cells. DAPI was used to stain nuclei. Scale bar, 20 μm. B. Quantitation of the number of apoptotic tubules (tubules containing ≥ 1 TUNEL positive cell). More than 200 tubules were scored for each sample.
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