PDF(Pubmed)
Abstract：
Introduction: TULP1 exemplifies the remarkable clinical and genetic heterogeneity observed in inherited retinal dystrophies. Our research describes the clinical and molecular characteristics of a patient manifesting an atypical retinal dystrophy pattern, marked by the identification of both a previously unreported and a rarely encountered TULP1 variant. Methods: Whole-exome sequencing was performed to identify potential causative variants. The pathogenicity of the identified TULP1 variants was evaluated through in silico predictors and a minigene splice assay, specifically designed to assess the effect of the unreported TULP1 variant. Results: We identified two TULP1 gene variants in a patient exhibiting unusual and symmetrical alterations in both retinas, characterized by an increase in autofluorescence along the distribution of retinal vessels. These variants included a known rare missense variant, c.1376T>C, and a novel splice site variant, c.822G>T. For the latter variant (c.822G>T), we conducted a minigene splice assay that demonstrated the incorporation of a premature stop codon. This finding suggests a likely activation of the nonsense-mediated mRNA decay mechanism, ultimately resulting in the absence of protein production from this allele. Segregation analysis confirmed that these variants were in trans. Discussion: Our data support that individuals with biallelic TULP1 variants may present with a unique pattern of macular degeneration and periarteriolar vascular pigmentation. This study highlights the importance of further clinical and molecular characterization of TULP1 variants to elucidate genotype-phenotype correlations in the context of inherited retinal dystrophies.
摘要：
简介：TULP1举例说明了遗传性视网膜营养不良中观察到的显着临床和遗传异质性。我们的研究描述了患者的临床和分子特征表现为非典型视网膜营养不良模式，以以前未报告和很少遇到的TULP1变体的鉴定为标志。方法：进行全外显子组测序以鉴定潜在的致病变异。通过计算机预测因子和小基因剪接测定来评估鉴定的TULP1变体的致病性。专门设计用于评估未报告的TULP1变体的效果。结果：我们在患者中发现了两个TULP1基因变异，在两个视网膜中都表现出异常和对称的改变，特征是沿着视网膜血管分布的自发荧光增加。这些变体包括一个已知的罕见错义变体，c.1376T>C，和一个新的剪接位点变异体,c.822G>T.对于后一种变体(c.822G>T)，我们进行了一项小基因剪接试验,证实了提前终止密码子的掺入.这一发现表明，无义介导的mRNA衰变机制可能被激活，最终导致该等位基因不产生蛋白质。分离分析证实这些变体是反式的。讨论：我们的数据支持具有双等位基因TULP1变体的个体可能表现出独特的黄斑变性和小动脉周围血管色素沉着模式。这项研究强调了TULP1变体的进一步临床和分子表征的重要性，以阐明遗传性视网膜营养不良背景下的基因型-表型相关性。
