A new candidate causative gene for high myopia has been discovered

High myopia (HM) patients account for 5.2% of the world's population and is one of the main causes of blindness. High myopia seriously affects the quality of life of patients. Genetic factors play an important role in the occurrence and development of HM. Although multiple pathogenic genes have been reported, the cause of more than half of hereditary HM patients remains unclear. Therefore, identifying and confirming the genetic and molecular basis of HM is conducive to providing guidance for early vision intervention and eye health management for these patients.

Recently, the research group led by Professor Shi Yi from the Affiliated Hospital of University of Electronic Science and Technology of China and Sichuan Provincial People's Hospital published a research paper in Science China Life Sciences, identifying LRRC46 as a new HM candidate pathogenic gene in the Han Chinese population.

Professor Shi Yi's research group recruited an autosomal dominant Chinese Han population HM family. Through exome sequencing and expanded sample verification, a nonsense mutation (C235T, p.Q79X) on the LRRC46 gene was found, which may be the pathogenic mutation of the family. The LRRC46 gene is located in the MYP5 (17q21-220) region, a reported myopia linkage site, and its encoded protein belongs to the leucine-rich repeat sequence (LRR) protein family. Many members of the LRR protein family are important components of the extracellular matrix (ECM) and are involved in the synthesis of collagen fibers. The cornea and sclera are the tissues with the highest content of collagen fibers in the eye, and the synthesis/arrangement of their collagen fibers is believed to play an important role in the occurrence and development of myopia. This study used multiple technical means such as human eye single-cell data set analysis, tissue section staining localization, and RT-PCR detection to clarify that the LRRC46 protein is significantly expressed in both the cornea and sclera. At the same time, Lrrc46 knockout mice (Lrrc46−/−) showed significant myopia. In addition to reduced refractive power and increased axial length, microstructural abnormalities on the sclera and cornea were also very significant. Transcriptome analysis showed that the signaling pathways related to ECM remodeling were significantly changed. Subsequent WB and q-PCR experiments also confirmed that the expression of collagen VIII (COL8A1), the core of the ECM remodeling pathway, was significantly reduced. In vitro experimental studies also found that knocking down LRRC46 would lead to reduced expression of collagen VIII and cytoskeletal abnormalities, which once again suggested that the loss of LRRC46 may promote the occurrence and development of myopia by affecting collagen formation.

Figure 1. Pedigree information of Chinese Han people with severe myopia and LRRC46 gene mutation.

Figure 2. Construction, identification and phenotypic analysis of Lrrc46-/- mice.

Figure 3. Structural differences between the sclera and cornea observed under electron microscopy.

This study suggests that LRRC46 is a new candidate pathogenic gene for HM. Experiments using Lrrc46−/− mice and cells have confirmed that the loss of this gene function will affect the synthesis of collagen in eye tissues, gradually changing the biomechanical structure of the cornea and sclera, thereby promoting the occurrence and development of HM. This study emphasizes the important role of LRRC46 in the pathogenesis of myopia.

For more details, please read the full article

Identification of LRRC46 as a novel candidate gene for high myopia

DOI: 10.1007/s1142‍7-024-2583-6