We report an early-onset autosomal-recessive neurological disease with cerebellar atrophy and lysosomal dysfunction. We identified bi-allelic loss-of-function (LoF) variants in Oxidative Resistance 1 (OXR1) in five individuals from three families; these individuals presented with a history of severe global developmental delay, current intellectual disability, language delay, cerebellar atrophy, and seizures. While OXR1 is known to play a role in oxidative stress resistance, its molecular functions are not well established. OXR1 contains three conserved domains: LysM, GRAM, and TLDc. The gene encodes at least six transcripts, including some that only consist of the C-terminal TLDc domain. We utilized Drosophila to assess the phenotypes associated with loss of mustard (mtd), the fly homolog of OXR1. Strong LoF mutants exhibit late pupal lethality or pupal eclosion defects. Interestingly, although mtd encodes 26 transcripts, severe LoF and null mutations can be rescued by a single short human OXR1 cDNA that only contains the TLDc domain. Similar rescue is observed with the TLDc domain of NCOA7, another human homolog of mtd. Loss of mtd in neurons leads to massive cell loss, early death, and an accumulation of aberrant lysosomal structures, similar to what we observe in fibroblasts of affected individuals. Our data indicate that mtd and OXR1 are required for proper lysosomal function; this is consistent with observations that NCOA7 is required for lysosomal acidification.

中文翻译：

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氧化抗性 1 (OXR1) 的丧失与伴有小脑萎缩和溶酶体功能障碍的常染色体隐性神经系统疾病相关。


我们报告了一种早发性常染色体隐性神经系统疾病，伴有小脑萎缩和溶酶体功能障碍。我们在来自三个家族的五个个体中发现了氧化抵抗 1 (OXR1) 的双等位基因功能丧失 (LoF) 变异；这些人有严重的整体发育迟缓、目前智力障碍、语言发育迟缓、小脑萎缩和癫痫发作的病史。虽然 OXR1 已知在抗氧化应激中发挥作用，但其分子功能尚未明确。 OXR1 包含三个保守结构域：LysM、GRAM 和 TLDc。该基因编码至少六个转录本，包括一些仅由 C 端 TLDc 结构域组成的转录本。我们利用果蝇来评估与芥末 (mtd) 损失相关的表型，芥末是 OXR1 的果蝇同源物。强 LoF 突变体表现出晚期蛹致死性或蛹羽化缺陷。有趣的是，尽管 mtd 编码 26 个转录本，但仅包含 TLDc 结构域的单个短人类 OXR1 cDNA 可以挽救严重的 LoF 和无效突变。 NCOA7（mtd 的另一个人类同源物）的 TLDc 结构域也观察到类似的拯救。神经元中 mtd 的丧失会导致大量细胞损失、早期死亡和异常溶酶体结构的积累，类似于我们在受影响个体的成纤维细胞中观察到的情况。我们的数据表明，mtd 和 OXR1 是正常溶酶体功能所必需的；这与 NCOA7 是溶酶体酸化所必需的观察结果一致。