LRP5 — LDL receptor related protein 5

The LRP5 gene provides instructions for making a protein that sits on the surface of many cells in the body. This protein acts like an antenna, receiving chemical signals from outside the cell and transmitting them inside. These signals are part of a communication system called the Wnt pathway, which is crucial for the proper development and maintenance of several tissues, particularly the blood vessels in the back of the eye (the retina) and the bones. When there is a mutation (a harmful change) in the LRP5 gene, the protein may not work correctly or may not be produced at all. If the signaling in the eye is disrupted, the blood vessels in the retina do not develop normally. This can lead to a condition called familial exudative vitreoretinopathy (FEVR), where the abnormal blood vessels can leak, scar, and potentially cause the retina to detach, leading to vision loss. Because LRP5 is also important for bone health, some mutations can cause the bones to be thin and fragile, a condition known as osteoporosis. The way LRP5 mutations affect families depends on the specific type of mutation. Sometimes, a person only needs one mutated copy of the gene (inherited from one parent) to develop FEVR. In other cases, a person must inherit two mutated copies (one from each parent) to be affected, which often results in a more severe condition called osteoporosis-pseudoglioma syndrome (OPPG), causing both severe vision loss from birth and brittle bones. Genetic testing can help determine the specific mutation and guide the care and screening for both eye and bone health.

Gene description: Encodes a transmembrane receptor involved in Wnt signaling and bone metabolism, with a role in retinal vascular development.

Patient and family guide: The LRP5 gene provides instructions for making a protein that sits on the surface of many cells in the body. This protein acts like an antenna, receiving chemical signals from outside the cell and transmitting them inside. These signals are part of a communication system called the Wnt pathway, which is crucial for the proper development and maintenance of several tissues, particularly the blood vessels in the back of the eye (the retina) and the bones. When there is a mutation (a harmful change) in the LRP5 gene, the protein may not work correctly or may not be produced at all. If the signaling in the eye is disrupted, the blood vessels in the retina do not develop normally. This can lead to a condition called familial exudative vitreoretinopathy (FEVR), where the abnormal blood vessels can leak, scar, and potentially cause the retina to detach, leading to vision loss. Because LRP5 is also important for bone health, some mutations can cause the bones to be thin and fragile, a condition known as osteoporosis. The way LRP5 mutations affect families depends on the specific type of mutation. Sometimes, a person only needs one mutated copy of the gene (inherited from one parent) to develop FEVR. In other cases, a person must inherit two mutated copies (one from each parent) to be affected, which often results in a more severe condition called osteoporosis-pseudoglioma syndrome (OPPG), causing both severe vision loss from birth and brittle bones. Genetic testing can help determine the specific mutation and guide the care and screening for both eye and bone health.

Gene function: LRP5 is a co-receptor for Wnt signaling pathways, crucial for various developmental processes, including retinal vascularization. In the retina, it plays a role in the normal development and maintenance of the retinal vasculature, ensuring proper blood supply to photoreceptors. Its dysfunction can lead to abnormal retinal vessel formation and subsequent photoreceptor degeneration, impacting visual function.

Protein structure: The LRP5 gene encodes a large, single-pass transmembrane protein consisting of 1,615 amino acids. The protein structure is characterized by a massive extracellular domain that makes up over 85% of the molecule, a short transmembrane segment, and a relatively small intracellular cytoplasmic tail. The extracellular domain contains four $\beta$-propeller motifs, each followed by an epidermal growth factor (EGF)-like domain, and three low-density lipoprotein receptor (LDLR) type A repeats. The $\beta$-propeller domains are critical for the protein's function, as they serve as the primary binding sites for Wnt ligands, the Norrin protein, and various Wnt antagonists such as DKK1 and Sclerostin. The intracellular domain contains multiple PPPSP motifs that become phosphorylated upon receptor activation, providing docking sites for the recruitment of Axin and the initiation of the downstream intracellular signaling cascade. The proper folding and membrane localization of LRP5 are essential for its role as a co-receptor in the Wnt/Norrin signaling pathways.

Molecular function: The LRP5 (Low-density lipoprotein receptor-related protein 5) gene encodes a transmembrane protein that functions as an essential co-receptor in the canonical Wnt and Norrin signaling pathways. At the cell surface, LRP5 forms a complex with the Frizzled-4 (FZD4) receptor and either Wnt ligands or the Norrin protein. This ligand-receptor interaction induces the phosphorylation of the intracellular domain of LRP5, which subsequently recruits Axin and the destruction complex away from $\beta$-catenin. The disassembly of the destruction complex prevents the degradation of $\beta$-catenin, allowing it to accumulate in the cytoplasm and translocate into the nucleus. In the nucleus, $\beta$-catenin interacts with TCF/LEF transcription factors to activate the expression of target genes involved in cell proliferation, differentiation, and survival. In the retina, the Norrin/FZD4/LRP5 signaling axis is specifically required for the development and maintenance of the retinal vasculature and the blood-retina barrier, as well as for the proper function of the retinal pigment epithelium (RPE).

Expression pattern: The LRP5 gene is widely expressed throughout the body, reflecting its fundamental role in Wnt signaling across various tissues. In the eye, LRP5 is prominently expressed in the developing and mature retina, particularly in the retinal vascular endothelial cells and the retinal pigment epithelium (RPE). Its expression is crucial during embryonic and early postnatal development for the proper formation and maturation of the retinal vascular network and the RPE monolayer. Beyond the eye, LRP5 is highly expressed in osteoblasts, where it plays a critical role in bone formation and the regulation of bone mineral density. It is also expressed in the inner ear, contributing to its vascularization, and in various other tissues including the liver, pancreas, and brain. The broad expression pattern of LRP5 underscores its pleiotropic effects and explains the combination of ocular and skeletal phenotypes observed in patients with LRP5 mutations.

Mutation spectrum: The mutation spectrum of the LRP5 gene is diverse, encompassing missense, nonsense, frameshift, and splice-site variants, as well as large genomic deletions. Over 100 pathogenic variants have been reported in association with LRP5-related disorders. Missense mutations are the most common type and are distributed throughout the extracellular domain of the protein, particularly within the $\beta$-propeller domains which are critical for ligand binding. Loss-of-function mutations, including truncating variants and large deletions, are typically responsible for the severe autosomal recessive osteoporosis-pseudoglioma syndrome (OPPG). In contrast, missense mutations that cause a partial reduction in Wnt/Norrin signaling are frequently identified in patients with autosomal dominant familial exudative vitreoretinopathy (FEVR). Gain-of-function missense mutations, which cluster in specific regions that interact with Wnt antagonists, are associated with high bone mass phenotypes.

Pathogenic variants: 1. p.Arg570Gln (c.1709G>A) - A well-characterized missense variant frequently associated with autosomal dominant familial exudative vitreoretinopathy (FEVR). 2. p.Gly610Arg (c.1828G>A) - A pathogenic missense variant reported in patients with autosomal recessive exudative vitreoretinopathy and osteoporosis-pseudoglioma syndrome (OPPG). 3. p.Val171Met (c.511G>A) - A classic gain-of-function missense variant that impairs the binding of Wnt antagonists, leading to autosomal dominant high bone mass syndrome. 4. p.Arg494Gln (c.1481G>A) - A missense variant identified in families with FEVR, demonstrating reduced Norrin signaling activity in functional assays. 5. p.Trp781* (c.2343G>A) - A nonsense variant resulting in premature protein truncation, associated with the severe OPPG phenotype when present in a biallelic state.

Clinical significance: Mutations in the LRP5 gene manifest clinically as two primary inherited retinal diseases: familial exudative vitreoretinopathy (FEVR) and osteoporosis-pseudoglioma syndrome (OPPG). FEVR is characterized by the incomplete development of the retinal vasculature, leading to peripheral retinal avascularity, neovascularization, exudation, and potentially retinal detachment and severe vision loss. The severity of FEVR is highly variable, ranging from asymptomatic individuals with mild peripheral vascular anomalies to severe cases presenting in infancy with bilateral retinal detachments and blindness. OPPG is a more severe, autosomal recessive condition that combines the ocular features of severe FEVR (often presenting as congenital or early-onset blindness due to retinal folds or detachments, sometimes misdiagnosed as pseudoglioma) with systemic skeletal abnormalities. Patients with OPPG exhibit extremely low bone mineral density (juvenile primary osteoporosis), leading to recurrent bone fractures starting in childhood. The ocular manifestations in OPPG are typically present at birth or early infancy, while the skeletal fragility becomes apparent as the child grows. Additionally, heterozygous LRP5 mutations can cause isolated juvenile primary osteoporosis or contribute to adult-onset osteoporosis without significant ocular involvement.

Inheritance: Autosomal Recessive

Chromosomal location: 11q13.2

Genotype-phenotype correlations: Genotype-phenotype correlations for LRP5 mutations are complex and depend significantly on the nature of the mutation and its effect on protein function. Biallelic loss-of-function mutations (such as nonsense, frameshift, or large deletions) that result in a complete absence of functional LRP5 protein typically cause the severe, early-onset osteoporosis-pseudoglioma syndrome (OPPG), characterized by both profound vision loss and severe juvenile osteoporosis. Heterozygous missense mutations that cause a partial loss of function or dominant-negative effect are more commonly associated with autosomal dominant familial exudative vitreoretinopathy (FEVR). The severity of FEVR in these cases can be highly variable, even within the same family, suggesting that other genetic modifiers or environmental factors may influence the phenotype. Interestingly, some specific missense mutations in the first $\beta$-propeller domain of LRP5 lead to a gain of function by preventing the binding of Wnt antagonists (like DKK1), resulting in high bone mass syndromes without ocular involvement.

Research and therapeutic approaches: Currently, there are no FDA-approved gene therapies or targeted pharmacological treatments specifically for LRP5-related inherited retinal diseases. The management of familial exudative vitreoretinopathy (FEVR) primarily involves surgical and laser interventions to address the complications of abnormal retinal vasculature. Prophylactic laser photocoagulation or cryotherapy is applied to the avascular peripheral retina to prevent neovascularization and exudation. In advanced stages with retinal detachment, surgical procedures such as vitrectomy or scleral buckling are required to preserve or restore vision. Research into targeted therapies is ongoing, largely focusing on the modulation of the Wnt/Norrin signaling pathway. Preclinical studies in Lrp5 knockout mouse models have explored the use of pharmacological Wnt activators, such as lithium chloride, which stabilizes $\beta$-catenin and has shown potential in normalizing retinal vascular development. Additionally, gene therapy approaches aiming to deliver functional LRP5 or Norrin via viral vectors are being investigated in animal models to restore signaling and prevent the progression of the vascular phenotype. For the skeletal manifestations of LRP5 mutations, standard osteoporosis treatments, including bisphosphonates, are often utilized to improve bone mineral density and reduce fracture risk.

Diagnostic testing: Diagnostic testing for LRP5 mutations typically involves targeted gene panel testing that includes LRP5 along with other genes associated with FEVR (such as FZD4, NDP, TSPAN12, and KIF11) and osteoporosis. Whole exome sequencing (WES) or whole genome sequencing (WGS) may also be employed, particularly when the clinical presentation is complex or when targeted panels fail to identify a causative variant. Sequence analysis can detect missense, nonsense, and splice-site variants, while deletion/duplication analysis is necessary to identify large genomic rearrangements. Genetic counseling is essential for families affected by LRP5 mutations due to the variable expressivity and different inheritance patterns associated with the gene. FEVR caused by LRP5 mutations can be inherited in an autosomal dominant or autosomal recessive manner, while OPPG is strictly autosomal recessive. Counseling should address the risk of recurrence, the potential for both ocular and skeletal manifestations, and the importance of clinical screening (such as wide-field fluorescein angiography for FEVR and bone mineral density scans for osteoporosis) for at-risk family members.

Animal models: The primary animal models used to study LRP5 function and its role in inherited retinal diseases are Lrp5 knockout (Lrp5-/-) mice. These mice accurately recapitulate the ocular phenotype seen in human familial exudative vitreoretinopathy (FEVR), developing abnormal retinal vasculature characterized by incomplete vascularization of the peripheral retina and the formation of abnormal capillary tufts. In addition to the ocular findings, Lrp5-/- mice exhibit low bone mineral density and persistent embryonic eye structures, mirroring the systemic features of osteoporosis-pseudoglioma syndrome (OPPG). Studies using these models have been crucial in elucidating the disease mechanisms, demonstrating that LRP5 deficiency leads to a loss of canonical Wnt/Norrin signaling, which is essential for normal retinal angiogenesis and the development of the retinal pigment epithelium (RPE). Furthermore, these models have been utilized to test potential therapeutic interventions, such as the pharmacologic activation of Wnt signaling using lithium, which has shown promise in normalizing the retinal vasculature in Lrp5-/- mice.

Population genetics: The carrier frequency of pathogenic LRP5 variants in the general population is relatively low, reflecting the rarity of LRP5-related inherited retinal diseases and severe skeletal dysplasias. However, specific variants may have higher frequencies in certain populations due to founder effects or genetic drift. For instance, large-scale sequencing studies in diverse cohorts have identified a broad spectrum of rare LRP5 variants, but no single predominant founder mutation has been universally recognized for FEVR or OPPG. Carrier screening for LRP5 is not typically included in standard reproductive carrier screening panels unless there is a known family history of FEVR, OPPG, or early-onset osteoporosis, or in populations where a specific founder variant has been identified.

Selected references: 1. Gong Y, et al. LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell, 2001. PMID: 11719181 2. Toomes C, et al. Mutations in LRP5 or FZD4 underlie the common familial exudative vitreoretinopathy locus on chromosome 11q. Am J Hum Genet, 2004. PMID: 15024691 3. Qin M, et al. Complexity of the genotype-phenotype correlation in familial exudative vitreoretinopathy with mutations in the LRP5 and/or FZD4 genes. Hum Mutat, 2005. PMID: 15981244 4. Boyden LM, et al. High bone density due to a mutation in LDL-receptor-related protein 5. N Engl J Med, 2002. PMID: 12015390 5. Ai M, et al. Clinical and molecular findings in osteoporosis-pseudoglioma syndrome. Am J Hum Genet, 2005. PMID: 16252235 6. Li JK, et al. Spectrum of Variants in 389 Chinese Probands With Familial Exudative Vitreoretinopathy. Invest Ophthalmol Vis Sci, 2018. PMID: 30372748 7. Xia CH, et al. A model for familial exudative vitreoretinopathy caused by LPR5 mutations. Hum Mol Genet, 2008. PMID: 18334578