Norwich Medical School, University of East Anglia, Rosalind Franklin Road, Norwich, UK.
Mol Vis. 2024 Mar 3;30:74-91. eCollection 2024.
Sorsby fundus dystrophy (SFD) is a rare, inherited form of macular degeneration caused by mutations in the gene encoding tissue inhibitor of metalloproteinases 3 (TIMP-3). There are 21 mutations currently associated with SFD, with some variants (e.g., Ser179Cys, Tyr191Cys, and Ser204Cys) having been studied much more than others. We review what is currently known about the identified SFD variants in terms of their dimerization, metalloproteinase inhibition, and impact on angiogenesis, with a focus on disparities between reports and areas requiring further study. We also explore the potential molecular mechanisms leading to the accumulation of extracellular TIMP-3 in SFD and consider how accumulated TIMP-3 causes macular damage. Recent reports have identified extraocular pathologies in a small number of SFD patients. We discuss these intriguing findings and consider the apparent discrepancy between the widespread expression of TIMP-3 and the primarily retinal manifestations of SFD. The potential benefits of novel experimental approaches (e.g., metabolomics and stem cell models) in terms of investigating SFD pathology are presented. The review thus highlights gaps in our current molecular understanding of SFD and suggests ways to support the development of novel therapies.
桑伯氏眼底营养不良症 (SFD) 是一种罕见的遗传性黄斑变性，由编码基质金属蛋白酶抑制剂 3 (TIMP-3) 的基因突变引起。目前与 SFD 相关的突变有 21 种，其中一些变体（例如 Ser179Cys、Tyr191Cys 和 Ser204Cys）的研究比其他变体要多得多。我们回顾了目前已知的 SFD 变体在二聚化、金属蛋白酶抑制和对血管生成的影响方面的情况，重点关注报告之间的差异和需要进一步研究的领域。我们还探讨了导致 SFD 中外源 TIMP-3 积累的潜在分子机制，并考虑了积累的 TIMP-3 如何导致黄斑损伤。最近的报告在少数 SFD 患者中发现了眼外病变。我们讨论了这些有趣的发现，并考虑了 TIMP-3 广泛表达与 SFD 主要视网膜表现之间的明显差异。还提出了新的实验方法（例如代谢组学和干细胞模型）在研究 SFD 病理方面的潜在益处。因此，该综述突出了我们目前对 SFD 分子理解的差距，并提出了支持新型治疗方法开发的方法。
