Abstract：
Biallelic pathogenic variants in TULP1 are mostly associated with severe rod-driven inherited retinal degeneration. In this study, we analyzed clinical heterogeneity in 17 patients and characterized the underlying biallelic variants in TULP1. All patients underwent thorough ophthalmological examinations. Minigene assays and structural analyses were performed to assess the consequences of splice variants and missense variants. Three patients were diagnosed with Leber congenital amaurosis, nine with early onset retinitis pigmentosa, two with retinitis pigmentosa with an onset in adulthood, one with cone dystrophy, and two with cone-rod dystrophy. Seventeen different alleles were identified, namely eight missense variants, six nonsense variants, one in-frame deletion variant, and two splice site variants. For the latter two, minigene assays revealed aberrant transcripts containing frameshifts and premature termination codons. Structural analysis and molecular modeling suggested different degrees of structural destabilization for the missense variants. In conclusion, we report the largest cohort of patients with TULP1-associated IRD published to date. Most of the patients exhibited rod-driven disease, yet a fraction of the patients exhibited cone-driven disease. Our data support the hypothesis that TULP1 variants do not fold properly and thus trigger unfolded protein response, resulting in photoreceptor death.
摘要：
TULP1的双等位基因致病变异主要与严重的杆驱动遗传性视网膜变性相关。在这项研究中,我们分析了17例患者的临床异质性,并对TULP1中潜在的双等位基因变异进行了表征.所有患者均接受了彻底的眼科检查。进行小基因测定和结构分析以评估剪接变体和错义变体的后果。三名患者被诊断为Leber先天性黑蒙，9例早发性视网膜色素变性,两个视网膜色素变性，在成年期发病，一个患有锥体营养不良，还有两个患有锥杆营养不良。鉴定出17个不同的等位基因,即八个错觉变体，六个废话变体，一个框内删除变体，和两个剪接位点变体。对于后两者，小基因分析显示包含移码和过早终止密码子的异常转录本。结构分析和分子建模表明错义变体的结构不稳定程度不同。总之,我们报告了迄今为止发表的最大的TULP1相关IRD患者队列.大多数患者表现出棒驱动的疾病，然而，一小部分患者表现出锥体驱动的疾病。我们的数据支持以下假设：TULP1变体不能正确折叠，从而触发未折叠的蛋白质反应。导致光感受器死亡。
