A recent study reports on the MESD gene as a novel disease gene associated with the condition of brittle bone disease, or osteogenesis imperfecta (OI). In this study, an international group of researchers led by scientists of the Institute of Human Genetics at Göttingen establish for the first time a link between MESD and a human disease. OI comprises a heterogeneous group of disorders characterized by bone fragility. The researchers investigated five unrelated families with a severe, progressive deforming type of OI whose affected members had multiple fractures and at least one had dental anomalies, and they identified homozygous mutations in MESD as the causative genetic defect. MESD serves in the endoplasmatic reticulum as a chaperone protein for the WNT signaling receptors LRP5 and LRP6 and assists their correct folding and trafficking to the cell membrane.

Subsequent functional analyses showed that, due to their position, the mutations did not entail full loss of MESD protein function, but they significantly reduced it. In the light of the clinical phenotypes described for humans and mice that are completely deficient of LRP5 or LRP6, the authors suggest that the cellular processes involved in bone mass accrual and dental patterning are especially sensible to reduced canonical WNT signaling. Increasing LRP5/LRP6-mediated WNT signaling by biological agents might therefore be a potential future strategy to treat patients with MESD-associated osteogenesis imperfecta.

The results of the studies were published in The American Journal of Human Genetics.