Three novel disease genes identified as drivers of a new form of hereditary retinal blindness
Researchers of the Institute of Molecular and Clinical Ophthalmology Basel (IOB), working with a broad international team, have identified mutations in three genes encoding subunits of the vesicular AP-5 complex as a new cause of hereditary macular dystrophy, a form of inherited retinal disease (IRD) that leads to progressive vision loss.
In this study published in the American Journal of Human Genetics (AJHG), they examined 22 affected individuals from 19 unrelated families, all of whom exhibited a consistent pattern of macular degeneration. Through comprehensive genetic analysis, the research team discovered that recessive variants in three genes—AP5Z1, AP5M1, and AP5B1—independently cause this specific form of hereditary blindness. These genes encode different subunits of the Fifth Adaptor Protein (AP-5) complex, which plays a crucial role in intracellular trafficking and maintaining proper lysosomal function.The retinal pigment epithelium (RPE) might be particularly affected by AP-5 complex dysfunction. The research team demonstrated that AP-5 proteins are present in the human RPE, and they co-localize with markers of late endosomes and the Golgi apparatus, suggesting their importance in normal cellular processes within this crucial tissue.
Lysosomal macular dystrophy
Based on these findings, the researchers propose classifying this condition as "lysosomal macular dystrophy", highlighting its connection to lysosomal storage diseases and providing a framework for future research and clinical management.
This work represents a significant step forward in addressing the "missing heritability" in IRDs, where approximately 20-50% of affected individuals still lack a definitive genetic diagnosis despite advances in genetic testing. By identifying the involvement of the AP-5 complex in macular health, this discovery not only expands our understanding of the genetic architecture of IRDs but also offers new diagnostic opportunities for individuals who have undergone prior genetic testing without receiving a conclusive result.
Graphical Abstract
Bi-allelic variants in three genes encoding distinct subunits of the vesicular AP-5 complex cause hereditary macular dystrophy, Kaminska, Karolina et al., The American Journal of Human Genetics
Source: IOB