Novel mutations affecting LRP5 splicing in patients with osteoporosis-pseudoglioma syndrome (OPPG)

摘要: Osteoporosis-pseudoglioma sydrome (OPPG) is an autosomal recessive disorder with early-onset severe osteoporosis and blindness, caused by biallelic loss-of-function mutations in the low-density lipoprotein receptor-related protein 5 (LRP5) gene. Heterozygous carriers exhibit a milder bone phenotype. Only few splice LRP5 have been published. We present clinical genetic data for four patients novel mutations, three of which affect splicing. Patients were evaluated clinically radiography densitometry. Genetic screening was performed on basis diagnosis OPPG. Splice aberrances confirmed cDNA sequencing or exon trapping. The effect one mutation function studied. A splice-site c.1584+4A>T abolished donor site 7 activated cryptic site, led to in-frame insertion 21 amino acids (p.E528_V529ins21). Functional studies revealed severely impaired signal transduction presumably defective intracellular transport mutated receptor. Exon trapping used two samples confirm that c.4112-2A>G c.1015+1G>T splicing-out exons 20 5, respectively. One patient carried homozygous deletion 4 causing loss as demonstrated analysis. Our results broaden spectrum provide first functional aberrations.