Importance Sorsby fundus dystrophy is a typically adult-onset maculopathy with high risk for choroidal neovascularization. Sorsby fundus dystrophy, inherited as an autosomal dominant fully penetrant trait, is associated with TIMP3 variants that cause protein aggregation in the extracellular matrix. Objective To evaluate the phenotype and underlying biochemical mechanism of disease-causing TIMP3 variants altering the N-terminal signal peptide in 2 families who have early-onset diffuse maculopathy without choroidal neovascularization with cosegregation of TIMP3 variants in the signal peptide sequence. Design, Setting, and Participants This case series of 2 families with early-onset diffuse maculopathy was conducted at the National Eye Institute, National Institutes of Health Clinical Center. Data were collected and analyzed from October 2009 to December 2021. Main Outcomes and Measures Clinical imaging and molecular genetic testing were performed in 2 families with macular dystrophy. Cosegregation analysis of TIMP3 variants was performed in affected and unaffected family members. Candidate TIMP3 signal peptide variants were assessed for cleavage defects after transfection. Results Eleven individuals from 2 families with early-onset diffuse maculopathy without choroidal neovascularization harbor TIMP3 variants (L10H or G12R) in the N-terminal signaling peptide were analyzed. Cosegregation with phenotype was confirmed in additional family members. Biochemical analysis confirmed defects in both protein maturation and extracellular deposition. Conclusions and Relevance This study found that TIMP3 variants altering signal peptide function deviated from classic Sorsby fundus dystrophy both in phenotypic features and underlying mechanism. These results suggest atypical patient presentations are caused by TIMP3 signal peptide defects, associated with impaired cleavage and deposition into the extracellular matrix, implicating a novel macular dystrophy disease.

中文翻译：

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与信号肽受损相关的早发性 TIMP3 相关视网膜病变。

重要性 Sorsby 眼底营养不良是一种典型的成人发病的黄斑病，具有脉络膜新生血管形成的高风险。Sorsby 眼底营养不良作为常染色体显性完全外显性状遗传，与导致细胞外基质中蛋白质聚集的 TIMP3 变异有关。目的 评估 TIMP3 变异体改变 N 末端信号肽的表型和潜在生化机制，这两个家族患有早发性弥漫性黄斑病变，无脉络膜新生血管，信号肽序列中 TIMP3 变异体共分离。设计、设置和参与者 本病例系列包括 2 个患有早发性弥漫性黄斑病变的家庭，是在美国国立卫生研究院临床中心的国立眼科研究所进行的。收集并分析了 2009 年 10 月至 2021 年 12 月的数据。主要结果和测量指标对 2 个黄斑营养不良家庭进行了临床影像学和分子遗传学检测。在受影响和未受影响的家庭成员中进行了 TIMP3 变体的共分离分析。在转染后评估候选 TIMP3 信号肽变体的切割缺陷。结果 分析了来自 2 个患有早发性弥漫性黄斑病变且无脉络膜新生血管的家庭的 11 名个体在 N 末端信号肽中具有 TIMP3 变体（L10H 或 G12R）。在其他家庭成员中证实了与表型的共分离。生化分析证实了蛋白质成熟和细胞外沉积的缺陷。结论和相关性 本研究发现，改变信号肽功能的 TIMP3 变体在表型特征和潜在机制上均不同于经典的 Sorsby 眼底营养不良。这些结果表明非典型患者表现是由 TIMP3 信号肽缺陷引起的，与细胞外基质的裂解和沉积受损有关，暗示了一种新型黄斑营养不良疾病。