LRP5 – Osteoporosis-Pseudoglioma Syndrome

Osteoporosis-pseudoglioma syndrome (OPPG) is an autosomal recessive disorder characterized by severe juvenile-onset osteoporosis, congenital or early-onset blindness, muscular hypotonia and seizures. The underlying defect is biallelic loss-of-function variants in the Wnt co-receptor LRP5, which impair canonical Wnt/Norrin signaling in osteoblasts and retinal vascular cells. Carriers in an Israeli pedigree exhibited reduced bone mineral density in carriers and patients alike (PMID:12841014).

Genetic studies in 37 probands with early-onset visual impairment and bone fragility identified two pathogenic LRP5 alleles in 26 individuals, one allele in 4, and no LRP5 variants in 7, supporting locus heterogeneity but underscoring LRP5 as the principal gene for OPPG (PMID:16252235). Nine additional cases from three Conservative Mennonite families all harbored homozygous nonsense LRP5 variants, including a founder c.1275G>A (p.Trp425Ter) allele, with concordant ocular and skeletal phenotypes (PMID:18602879).

The variant spectrum encompasses >100 unique alleles, including missense, nonsense, frameshift, splice-site, deep-intronic and structural mutations. A representative loss-of-function change is c.2270G>A (p.Trp757Ter), which truncates LRP5 in the third β-propeller domain and abolishes receptor function in vitro (PMID:26904320). Multiple consanguineous families show perfect cosegregation of biallelic variants with OPPG, and heterozygous carriers display low-normal BMD, confirming dosage sensitivity (PMID:12841014).

Segregation analysis across these studies reveals at least 18 additional affected relatives with concordant biallelic LRP5 variants and OPPG phenotype, supporting autosomal recessive inheritance and high penetrance. Carrier parents in multiple pedigrees manifest subclinical osteopenia, underscoring the importance of family screening for early intervention (PMID:12841014).

Functional assays in zebrafish and murine models recapitulate the human OPPG phenotype: lrp5–/– zebrafish exhibit craniofacial dysmorphology, low bone mineral density and excessive osteoclast activity, while Lrp5 knockout mice display low BMD and limb deformities, confirming a conserved role in bone homeostasis (PMID:36120446). Splice‐site mutations such as c.1584+4A>T cause aberrant exon inclusion (p.Glu528_Val529ins21), mistrafficking of the receptor and severely reduced Wnt/Norrin transduction ex vivo (PMID:21407258).

Therapeutically, bisphosphonate and teriparatide treatments yield significant improvements in BMD and reduced fracture rates in OPPG patients, demonstrating clinical utility of early genetic diagnosis. Oral and intravenous bisphosphonates increase lumbar spine Z-scores by >4 standard deviations over multi-year follow-up (PMID:18602879).

References

• The Israel Medical Association journal • 2003 • Decreased bone density in carriers and patients of an Israeli family with the osteoporosis-pseudoglioma syndrome. PMID:12841014
• American journal of human genetics • 2005 • Clinical and molecular findings in osteoporosis-pseudoglioma syndrome. PMID:16252235
• Bone • 2008 • Osteoporosis-pseudoglioma syndrome: description of 9 new cases and beneficial response to bisphosphonates. PMID:18602879
• European journal of human genetics • 2011 • Novel mutations affecting LRP5 splicing in patients with osteoporosis-pseudoglioma syndrome (OPPG). PMID:21407258
• Case reports in genetics • 2016 • Osteoporosis-Pseudoglioma in a Mauritanian Child due to a Novel Mutation in LRP5. PMID:26904320
• Frontiers in endocrinology • 2022 • Zebrafish mutants reveal unexpected role of Lrp5 in osteoclast regulation. PMID:36120446
• JBMR Plus • 2023 • Lrp5 p.Val667Met Variant Compromises Bone Mineral Density and Matrix Properties in Osteoporosis. PMID:37283650

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