A novel mutation in the LRP5 gene is associated with osteoporosis-pseudoglioma syndrome

Dear Editor, Osteoporosis-pseudoglioma syndrome (OPPG) is an autosomal recessive disorder characterized by low bone mass and ocular globe alterations, with frequent fractures as a consequence of high skeletal fragility and severe visual deficiency [1]. Recently, Gong et al. identified mutations in the low-density lipoprotein receptor-related protein 5 gene (LRP5) that cause OPPG [2]. The LRP5 gene is located on the long arm of chromosome 11 at 11q13.4, has 23 exons, and encodes a transmembrane protein with 1,615 amino acids. This protein is a member of the low-density lipoprotein receptor (LDLR) family, the members of which have very well conserved characteristics. We had the opportunity to follow-up two brothers with clinical characteristics of OPPG, and we decided to investigate the LRP5 gene to identify any mutation that could explain the clinical features of low bone mass, fractures, and blindness. The older brother came to the hospital when he was 12 years old, (53 kg; 157 cm). At that time, lumbar bone mineral density (BMD, Hologic 4,500 A) was 0.512 g/cm (Z score −3.99). He was born blind, had a normal development until the age of 7 years, when he had lumbar pain due to the fracture of a vertebral body. At the age of 11, pain in the left leg led to the diagnosis of a tibial fracture. One month later, the same occurred in the right tibia and 2 months after that, a fracture in the right femur was detected, and he was referred to our hospital. The younger brother was 4 years old at that time and was born blind. At 2.5 years, he had a fracture of the right femur after a small fall. He was eutrophic (13 kg and 97 cm), with a lumbar BMD of 0.277 g/cm2 (Z score −5.4). Both of them had normal biochemical and hormonal parameters. Their parents were consanguineous, had normal BMD and no history of fractures or blindness, and there were no similar cases in the family. The 23 exons were analyzed and we identified an LPR5 missense mutation in the third codon of exon 8, in which an asparagine is replaced by isoleucine (N531I) in two siblings with OPPG and their consanguineous parents. The patients were found to be homozygous for this mutation, while their parents are heterozygous. This amino acid is located at the second propeller domain (YWTD repeat) in the extracellular domain of the receptor. Fifty normal participants underwent analysis of this exon, and the mutation was not present in any of them, but a polymorphism C→T (rs545382 NCBI, F549F) was found at a frequency of 1:5. According to Sidow’s program [3] of multivariate analysis of protein polymorphism (MAPP), we observed that the N531I mutant scored higher (yielding a bad amino acid substitution) and this mutation is located in the group of deleterious variants because of its high degree of evolutionary conservation. Based on these facts, we believe that this mutation is responsible for the clinical features presented in our patients and thereby define a novel mutation that causes OPPG in humans. Osteoporos Int DOI 10.1007/s00198-007-0360-x