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.
School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, QLD, 4072, Australia.
Cerebellum. 2019 Jun;18(3):448-456. doi: 10.1007/s12311-019-01012-w.
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.
眼动运动不能型 2 型共济失调（AOA2）是一种罕见的常染色体隐性小脑共济失调，发病年龄在 10 至 20 岁之间，具有多种神经系统特征，包括进行性小脑萎缩、轴索性感觉运动神经病、大多数患者的眼动运动不能以及血清甲胎蛋白（AFP）升高。AOA2 是由 SETX 基因突变引起的，该基因编码参与转录调节、RNA 加工和 DNA 维持的 senataxin。在啮齿动物中破坏 senataxin 导致雄性的精子发生缺陷和不育，揭示了 senataxin 在雄性生殖细胞存活中的关键作用。在这里，我们报告了 AOA2 患者精子发生受损的首例临床和细胞证据。我们评估了 3 名 AOA2 患者的精子生成情况和 1 名患者的睾丸病理，并将这些发现与 Setx 敲除小鼠进行了比较。所有评估的患者（3/3，100%）的精子生成均受损。对 AOA2 患者睾丸活检的分析再现了 Setx 敲除小鼠中所见的组织学特征，强烈表明潜在的机制集中在 DNA 损伤介导的生殖细胞凋亡上。这些发现支持 senataxin 在人类生殖功能中的作用，并强调了 AOA2 的一个新的临床特征，即超出了 senataxin 的神经外作用。这为临床医生提出了一个重要的生殖咨询问题，并且生育专家应该意识到 SETX 突变可能是年轻男性患者出现少精症或无精症的一个诊断，因为在某些个体中，不育可能预示着以后会出现神经表现。
