One family with osteosclerosis caused by D111Y mutation in the low-density lipoprotein receptor-related protein 5 gene

Objective To investigate the clinical features and pathogenic genes of a family with osteosclerosis. Methods Six patients and six family members from a family in Jiangsu were tested for biochemical parameters, bone metabolic markers, bone mineral density, thoracolumbar anterior lateral slices, skull positive lateral radiographs, and pelvic plain films. Meanwhile, Sanger sequencing was performed to detect gene mutations of the proband and five other family members with high bone mass. The conformation of the mutational low-density lipoprotein receptor-related protein 5 (LRP5) protein was predicted by SWISS-MODEL. Results Four adult patients (one male and three females) were tall, with mandibular enlargement and kyphosis in the center of the lower jaw, and none of the four had fractures. Their X ray examination revealed that the skull and long bone cortex was thickened, while the sella and mandible was enlarged. In addition, the absolute values of bone mineral density at each site of all patients were significantly higher as compared with the standard age- and sex-matched adults or adolescent mean reference values, with Z scores of L2-4, femoral neck and total hip being (6.31±4.03) SD, (6.56±2.36) SD, and (7.19±2.03) SD, respectively. The results of genetic sequencing revealed that all six patients carried a heterozygous mutation (c.331G>T; D111Y) in exon 2 of LRP5 gene, while other family members showed wild type (c.331G>G; D111D). Functional prediction indicated that this mutation was located at the amino acid terminal of exon 2 of LRP5 gene, which encodes the first β-helix-generating region of LRP5 protein. Conclusion The D111Y mutation in LRP5 gene leads to a clinical phenotype characterized by benign increased bone mineral density without increasing the risk of fracture. This mutation may further affect the downstream Wnt signaling pathway by altering the spatial structure of LRP5 protein, thereby promoting maturation and differentiation of osteoblasts and resulting in osteosclerosis. Key words: Osteosclerosis; Low-density lipoprotein receptor-related protein 5; Gain of function; Wnt signaling pathway