Targeted deletion of Wnt1 in mesenchymal progenitors led to spontaneous fractures due to impaired osteoblast function and increased bone resorption, mimicking the severe OI phenotype in humans with homozygous WNT1 mutations.
Those cases typically appear to represent vascular disruptions, and we suggest that most brain anomalies in WNT1-associated OI have vascular origins related to a role for WNT1 in CNS angiogenesis.
Thorough revision of the clinical symptoms of these 10 novel patients and previously published AR WNT1OI cases highlight ptosis as a unique hallmark in the diagnosis of this OI subtype.
We report a novel mutation responsible for OI and our investigation expands the spectrum of disease-causing WNT1 mutations and the resulting OI phenotypes.
This report emphasizes the intrafamilial variability of brain anomalies found in this OI type and suggests that WNT1 may not be necessary for normal human cognitive development.
The rest of the cases, however, involve many other noncollagen genes, all of which are autosomal-recessively inherited, except for IFITM5 and WNT1, which are also associated with autosomal dominant OI.
Although the pathogenic mechanism of WNT1 defects in OI has yet to be uncovered, these findings further contribute to the implications and importance of functional relevance of WNT1 in skeletal disorders.
Collectively, our data suggest that WNT1-related OI and osteoporosis are caused in part by decreased mTORC1-dependent osteoblast function resulting from loss of WNT1 signaling in osteocytes.
Recently, WNT1 is identified as a new candidate gene for OI, here we detect pathogenic mutations in WNT1 and analyze the genotype-phenotype association in four Chinese families with OI.
Intravenous bisphosphonate treatment of four children with homozygous or compound heterozygous WNT1 mutations was associated with increasing lumbar spine areal bone mineral density z-scores, as measured by dual energy X-ray absorptiometry, but the effect was smaller than what had previously been reported for children with classical osteogenesis imperfecta.
Our study thus provides in vivo evidence that WNT1 mutations contribute to bone fragility in OI patients and demonstrates that the Wnt1(sw/sw) mouse is a murine model of OI caused by WNT1 mutations.
We report that hypofunctional alleles of WNT1 cause autosomal-recessive osteogenesis imperfecta, a congenital disorder characterized by reduced bone mass and recurrent fractures.
Here, we describe four recessive-OI-affected families in which we identified causative mutations in wingless-type MMTV integration site family 1 (WNT1).