Bone Mineral Density Quantitative Trait Locus 16

A number sign (#) is used with this entry because of evidence that susceptibility to early-onset autosomal dominant osteoporosis can be conferred by heterozygous mutation in the WNT1 (164820) gene on chromosome 12q13.

Clinical Features

Keupp et al. (2013) described a 4-generation family segregating early-onset osteoporosis and fractures inherited in an autosomal dominant pattern. Affected family members showed recurrent fractures (e.g., of vertebrae and ribs after minor trauma) beginning in adolescence, low-bone-turnover markers, and a reduction of trabecular and cortical bone as revealed by high-resolution CT.

Mapping

Laine et al. (2013) performed a genomewide microsatellite linkage analysis with the use of DNA from 10 affected and 6 healthy members of a Finnish family segregating autosomal dominant early-onset osteoporosis and identified one putative linkage area of 25.5 Mb on chromosome 12 that included the WNT1 gene.

Molecular Genetics

By whole-exome sequencing of 2 affected individuals from a 4-generation family segregating autosomal dominant early-onset osteoporosis and fractures, Keupp et al. (2013) identified a heterozygous missense mutation in the WNT1 gene (R235W; 164820.0007) that segregated with the phenotype in the family. Bone-density measurements in the parents of 2 patients with recessive osteogenesis imperfecta XV (615220) resulting from a homozygous deletion mutation in the WNT1 gene (164820.0001) showed that 1 heterozygous father had signs of osteoporosis at age 42, whereas the other 3 heterozygous parents had low normal measurements. Keupp et al. (2013) demonstrated that altered WNT1 proteins failed to activate canonical LRP5-mediated WNT-regulated beta-catenin signaling. In addition, osteoblasts cultured in vitro showed enhanced Wnt1 expression with advancing differentiation, indicating a role of WNT1 in osteoblast function and bone development.

In affected members of a Finnish family segregating early-onset osteoporosis mapping to chromosome 12, Laine et al. (2013) identified a heterozygous mutation in the WNT1 gene (C218G; 164820.0009). Laine et al. (2013) demonstrated that, in vitro, aberrant forms of the WNT1 protein showed impaired capacity to induce canonical WNT signaling, their target genes, and mineralization. Laine et al. (2013) also showed that mouse Wnt1 was clearly expressed in bone marrow, especially in B-cell lineage and hematopoietic progenitors; lineage tracing identified the expression of the gene in a subset of osteocytes, suggesting the presence of altered cross-talk in WNT signaling between the hematopoietic and osteoblastic lineage cells in osteoporosis and in OI type XV (615220).