Original Full Length ArticleSkeletal characteristics associated with homozygous and heterozygous WNT1 mutations☆
Introduction
Osteogenesis imperfecta (OI) is a heritable disorder associated with increased bone fragility. OI is usually due to dominant mutations in COL1A1 or COL1A2, but recessive forms of OI, caused by mutations in genes involved in various aspects of bone formation, have been described as well [1]. We and others recently found that mutations in WNT1 can give rise to a recessive bone fragility disorder [2], [3], [4], [5]. The WNT signaling pathway is one of the key regulators of osteoblast activity [6].
The skeletal effects of WNT1 mutations that are associated with recessive bone fragility remain incompletely characterized. Even though bone histomorphometric data have been presented on three carriers of heterozygous WNT1 mutations in families with dominant osteoporosis [5], the bone tissue and material characteristics resulting from homozygous WNT1 mutations have not been reported. It is also not clear whether patients with homozygous WNT1 mutations benefit from treatment with bisphosphonates, which are widely used in children with OI [7].
The effect of heterozygous WNT1 mutations also requires further characterization. Two families with dominant early-onset osteoporosis caused by heterozygous WNT1 mutations have been reported [3], [5]. These families were unrelated to the kindreds where recessive bone fragility caused by homozygous WNT1 mutations was observed. It is unclear from these reports whether WNT1 mutations that lead to recessive bone fragility also cause dominant osteoporosis in mutation carriers.
Nevertheless, the available reports on children with recessive bone fragility caused by homozygous WNT1 mutations mentioned that dual-energy X-ray absorptiometry had been performed on a total of eight parents who were heterozygous WNT1 mutation carriers [3], [4], [5]. Among these, one heterozygous father was said to have had ‘early-onset osteoporosis’, but details were not given [3]. Another father had a lumbar spine areal bone mineral density (BMD) z-score of − 1.8 at 43 years and had a mild compression fracture of a lumbar vertebra [5]. It is thus possible that the parents of children with bone fragility due to WNT1 mutations are at risk of having osteoporosis.
In the present study, we assessed four children from three unrelated families who had homozygous or compound heterozygous WNT1 mutations. We analyzed iliac bone samples from three of these children using histomorphometry and quantitative backscattered electron imaging. In addition, we assessed the effect of intravenous bisphosphonate therapy on spine development. Finally, we also evaluated six heterozygous WNT1 mutation carriers from two of these families.
Section snippets
Subjects
All study participants were assessed at the Shriners Hospital for Children in Montreal. Children with homozygous or heterozygous WNT1 mutations were followed for medical, surgical and rehabilitative care. Clinical data were extracted by retrospective chart review.
Family members of children with WNT1 mutations were assessed on one occasion only, for the purpose of the present study. The study was approved by the Institutional Review Board of McGill University. Informed consent was provided by
Functional characterization of WNT1 mutations
WNT1 mutations were found in four children from three unrelated families (Fig. 1A; Table 1), as previously reported [2]. In Family 1, both children (F1-IV.1 and F1-IV.2) had a homozygous missense mutation (p.Cys143Phe), whereas in Family 2 the affected child (F2-II.1) was homozygous for a frameshift mutation (p.Gln96Profs*54). The child in Family 3 (F3-II.1) was compound heterozygous for a frameshift mutation (p.Ser317Lysfs153) and a missense mutation (p.Val355Phe). The two frameshift mutations
Discussion
In this study we found that children with homozygous or compound heterozygous loss of function mutations in WNT1 did not have major abnormalities in either the bone lamellation pattern or the BMDD in iliac bone samples. Intravenous bisphosphonate treatment was associated with a small increase in LS-aBMD and reshaping in some vertebral bodies. Heterozygous WNT1 mutation carriers from the same family tended to have low bone mass and several of these mutation carriers had radiographic signs of
Acknowledgments
We thank Patty Mason for the technical assistance with laboratory experiments, Mark Lepik for preparing the figures and Marie-Josée Giguère for the project supervision. H.A. was supported by a postdoctoral fellowship from the Network for Oral and Bone Health Research (RSBO) of the Fonds de recherche du Québec — Santé. F.R. received salary support from the Chercheur-Boursier Clinicien program of the Fonds de recherche du Québec — Santé. In addition, this study was supported by the Shriners of
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