Lrpap1-flox Mouse

Lrpap1, also known as receptor associated protein (RAP), is an endoplasmic reticulum chaperone and inhibitor of LDL receptor related protein 1 (LRP1) and related receptors [2]. It is involved in ensuring proper formation of intermolecular disulfide bonds during biogenesis of low density lipoprotein (LDL) receptors and acts as an escort protein during trafficking through the endoplasmic reticulum and early Golgi compartment, preventing premature receptor-ligand interaction [4]. It has a general influence on lipid metabolism and is expressed in various tissues including the developing neural system, eye, ear, branchial arches, skin, and pronephric kidney [4].

Frameshift mutations in Lrpap1 lead to autosomal recessive high myopia in humans. In a zebrafish lrpap1 mutant line generated by CRISPR/Cas9 technology, the mutant showed a myopic phenotype with larger eye axial length-to-body length, myopic shift, and disordered scleral collagen fibers. RNA sequencing indicated activation of apoptosis signaling, likely due to elevated TGF-β protein expression. Treatment with a TGF-β agonist aggravated eyeball apoptosis in wild-type embryos, while a TGF-β inhibitor mitigated apoptosis in mutant embryos [1]. In a 9-year-old girl with a homozygous LRPAP1 pathogenic variant, myopic foveoschisis developed, evolving into a lamellar macular hole [3]. A homozygous LRPAP1 knockout human embryonic stem cell line was generated to study mechanisms of retinal degeneration underlying LRPAP1 deficiency [5]. Also, Lrpap1 deficiency may play a role in the development of myopia through TGF-β-induced apoptosis [1].

In conclusion, Lrpap1 plays a crucial role in maintaining normal eye development and refractive state, likely through its influence on apoptosis signaling mediated by TGF-β. The study of Lrpap1 knockout models in zebrafish and humans provides insights into the mechanisms underlying myopia development, especially in cases related to LRPAP1-associated myopia.