These observations suggest that more effective treatment approaches are needed for children with recessive WNT1-related bone fragility and that a systematic work-up for osteoporosis is warranted for WNT1 mutation carriers in these families.
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.
Human genetic evidence demonstrates that WNT1 mutations cause osteogenesis imperfecta (OI) and early-onset osteoporosis, implicating WNT1 as a major regulator of bone metabolism.
Cohort comprised mutation-positive (N = 13; age 17-76 years) and mutation-negative (N = 13; 16-77 years) subjects from two Finnish families with autosomal dominant WNT1osteoporosis due to a heterozygous missense mutation c.652T>G (p.C218G) in WNT1.
The implication of WNT1 in the control of bone formation identifies a potential new target for the treatment of low bone mass disorders, such as osteoporosis.
Here we report clinical findings of the WNT1osteoporosis in 8 children and young adults (median age 14 years; range 10 to 30 years) in two families, all with the p.C218G mutation in WNT1.
Altogether, 12 mutation-positive (MP) subjects (median age, 39 years; range, 11 to 76 years) and 12 mutation-negative (MN) subjects (35 years; range, 9 to 59 years) from two Finnish families with WNT1osteoporosis due to the heterozygous p.C218GWNT1 mutation.
The identification of Wnt1 as a regulator of bone formation and remodeling provides the basis for development of Wnt1-targeting drugs for the treatment of osteoporosis.
To evaluate the relationship between osteocyte-specific protein expression and bone histology in patients with monogenic osteoporosis due to wingless integration site 1 (WNT1) or plastin 3 (PLS3) mutations.
Patients carrying homozygous WNT1 mutations have more frequent fractures while heterozygous carriers of the mutation in WNT1 gene are also found to have early onset osteoporosis.
In addition, in a family affected by dominantly inherited early-onset osteoporosis, a heterozygous WNT1 missense mutation was identified in affected individuals.
In 10 family members with dominantly inherited, early-onset osteoporosis, we identified a heterozygous missense mutation in WNT1, c.652T→G (p.Cys218Gly).