National Eye Institute, National Institutes of Health, Bethesda, Maryland.
JAMA Ophthalmol. 2022 Jul 1;140(7):730-733. doi: 10.1001/jamaophthalmol.2022.1822.
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.
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.
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.
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.
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.
Sorsby 眼底营养不良是一种典型的成人发病的黄斑病变，具有发生脉络膜新生血管的高风险。Sorsby 眼底营养不良作为一种常染色体显性完全外显的特征遗传，与 TIMP3 变异有关，这些变异导致细胞外基质中的蛋白质聚集。
评估改变 TIMP3 信号肽 N 端序列的致病变异导致疾病的表型和潜在生化机制，这两种变异在两个家族中均存在早期弥漫性黄斑病变而无脉络膜新生血管，且 TIMP3 信号肽序列中的变异存在共分离。
设计、设置和参与者：本病例系列研究了 2 个具有早期弥漫性黄斑病变的家族，在国立眼科研究所、美国国立卫生研究院临床中心进行。数据收集和分析于 2009 年 10 月至 2021 年 12 月进行。
对 2 个黄斑营养不良家族进行了临床成像和分子遗传检测。对受影响和未受影响的家族成员进行了 TIMP3 变异的共分离分析。评估候选 TIMP3 信号肽变异在转染后的切割缺陷。
分析了 2 个具有早期弥漫性黄斑病变而无脉络膜新生血管的家族中 11 名个体的 TIMP3 变异（L10H 或 G12R）位于 N 端信号肽。在其他家族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。
本研究发现，改变信号肽功能的 TIMP3 变异在表型特征和潜在机制上均与经典 Sorsby 眼底营养不良不同。这些结果表明，TIMP3 信号肽缺陷导致非典型患者表现，与切割受损和沉积到细胞外基质有关，提示一种新的黄斑营养不良疾病。
