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Germline mutations in WTX cause a sclerosing skeletal dysplasia but do not predispose to tumorigenesis


Abnormalities in WNT signaling are implicated in a broad range of developmental anomalies and also in tumorigenesis1. Here we demonstrate that germline mutations in WTX (FAM123B), a gene that encodes a repressor of canonical WNT signaling2, cause an X-linked sclerosing bone dysplasia, osteopathia striata congenita with cranial sclerosis (OSCS; MIM300373)3. This condition is typically characterized by increased bone density and craniofacial malformations in females and lethality in males. The mouse homolog of WTX is expressed in the fetal skeleton, and alternative splicing implicates plasma membrane localization of WTX as a factor associated with survival in males with OSCS. WTX has also been shown to be somatically inactivated in 11–29% of cases of Wilms tumor4,5,6. Despite being germline for such mutations, individuals with OSCS are not predisposed to tumor development. The observed phenotypic discordance dependent upon whether a mutation is germline or occurs somatically suggests the existence of temporal or spatial constraints on the action of WTX during tumorigenesis.

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Figure 1: Phenotype of the proband (case 06) and delineation of her de novo chromosomal deletion within Xq11.
Figure 2: Functional domains within WTX and alternative splice forms in relation to sites of point mutations associated with OSCS and Wilms tumor.
Figure 3: Expression pattern of Wtx in the E14.5 mouse embryo.
Figure 4: Expression and biochemical properties of the alternatively spliced isoforms of WTX.

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The investigators are grateful for the generosity of the individuals and families with OSCS for their participation in this work. Thanks to A. Reeve, J. Matheson and P. Daniel for comments on the manuscript, A. Wilkie and C. Beck for discussions and R. McPhee for assistance with manuscript preparation. S.P.R. is supported by the Child Health Research Foundation of New Zealand and Lotteries Health New Zealand.

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Authors and Affiliations



Z.A.J. conceived, designed and performed the experiments addressing WTX functions and co-wrote the paper; M.v.K. analysed the microarray data, conceived and performed experiments validating genomic deletions and co-wrote the manuscript; T.M. performed and validated mutation detection; A.J. and R.F. assisted in qPCR and MLPA design and execution; E.P. and C.T. designed and performed the in situ hybridization analysis; A.V.H., M.E.P., S.G.-M., A.B., D.L., F.S., T.F., L.B., S.B., L.C.A., M.T., A.D., L.C.W., R.C.M.H., D.D., S.M. and V.C.-D. ascertained affected individuals, and evaluated and characterized their phenotypes; and S.P.R. led the project, conceived and designed experiments and wrote the paper.

Corresponding author

Correspondence to Stephen P Robertson.

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Competing interests

The corresponding author has filed a provisional patent for the application of insights gained from this study. The patent refers to exploiting the properties of WTX with the aim of improving bone quality and structure.

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Supplementary Figures 1–5, Supplementary Tables 1 and 2 and Supplementary Methods (PDF 956 kb)

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Jenkins, Z., van Kogelenberg, M., Morgan, T. et al. Germline mutations in WTX cause a sclerosing skeletal dysplasia but do not predispose to tumorigenesis. Nat Genet 41, 95–100 (2009).

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