In murine and canine animal models, mutations in the Arylsulfatase G gene (ARSG) cause a particular lysosomal storage disorder characterized by neurological phenotypes. Recently, two variants in the same gene were found to be associated with an atypical form of Usher syndrome in humans, leading to visual and auditory impairment without the involvement of the central nervous system. In this study, we identified three novel pathogenic variants in ARSG, which segregated recessively with the disease in two families from Portugal. The probands were affected with retinitis pigmentosa and sensorineural hearing loss, generally with an onset of symptoms in their fourth decade of life. Functional experiments showed that these pathogenic variants abolish the sulfatase activity of the Arylsulfatase G enzyme and impede the appropriate lysosomal localization of the protein product, which appears to be retained in the endoplasmic reticulum. Our data enable to definitely confirm that different biallelic variants in ARSG cause a specific deaf‐blindness syndrome, by abolishing the activity of the enzyme it encodes.

中文翻译：

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将 ARSG 突变与 Usher 综合征 IV 型联系起来的新临床和分子证据

在鼠类和犬类动物模型中，芳基硫酸酯酶 G 基因 ( ARSG ) 的突变会导致以神经表型为特征的特定溶酶体贮积症。最近，发现同一基因中的两个变体与人类非典型形式的 Usher 综合征有关，在不涉及中枢神经系统的情况下导致视觉和听觉障碍。在这项研究中，我们在ARSG中发现了三种新的致病变异，在来自葡萄牙的两个家庭中隐性地与疾病隔离。先证者患有色素性视网膜炎和感觉神经性听力损失，通常在其生命的第四个十年出现症状。功能实验表明，这些致病变异消除了芳基硫酸酯酶 G 酶的硫酸酯酶活性，并阻碍了似乎保留在内质网中的蛋白质产物的适当溶酶体定位。我们的数据能够通过消除其编码的酶的活性，明确证实ARSG中的不同双等位基因变异会导致特定的耳聋综合征。