期刊
BONE
卷 67, 期 -, 页码 63-70出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.bone.2014.06.041
关键词
Backscattered electron imaging; Bone fragility; Osteogenesis imperfecta; Osteoporosis; Vertebral fractures; WNT1
资金
- Network for Oral and Bone Health Research (RSBO) of the Fonds de recherche du Quebec - Sante
- Chercheur-Boursier Clinicien program of the Fonds de recherche du Quebec - Sante
- Shriners of North America [85400-CAN]
- AUVA [X07023]
- WGKK [AR-657]
Recent reports have shown that homozygous or compound heterozygous mutations in WNT1 can give rise to severe bone fragility resembling osteogenesis imperfecta, whereas heterozygous WNT1 mutations have been found in adults with dominant early-onset osteoporosis. Here we assessed the effects of WNT1 mutations in four children with recessive severe bone fragility and in heterozygous family members. In vitro studies using the Topflash luciferase reporter system showed that two WNT1 missense mutations that were observed in these families, p.Cys143Phe and p.Val355Phe, decreased the ability of WNT1 to stimulate WNT signaling by >90%. Analyses of iliac bone samples revealed no major abnormalities in bone mineralization density distribution, an indicator of material bone properties, whereas a shift towards higher bone mineralization density is characteristic of classical osteogenesis imperfecta caused by mutations in COL1A1/COL1A2. 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. Family members with heterozygous WNT1 mutation tended to have low bone mass. Three of these heterozygous individuals had radiographic signs of vertebral fractures. 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. (C) 2014 Elsevier Inc. All rights reserved.
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