Brachydactyly type A1 (BDA1) was the first recorded disorder of the autosomal dominant Mendelian trait in humans, characterized by shortened or absent middle phalanges in digits. It is associated with heterozygous missense mutations in indian hedgehog (IHH)1,2. Hedgehog proteins are important morphogens for a wide range of developmental processes3,4. The capacity and range of signalling is thought to be regulated by its interaction with the receptor PTCH1 and antagonist HIP1. Here we show that a BDA1 mutation (E95K) in Ihh impairs the interaction of IHH with PTCH1 and HIP1. This is consistent with a recent paper showing that BDA1 mutations cluster in a calcium-binding site essential for the interaction with its receptor and cell-surface partners5. Furthermore, we show that in a mouse model that recapitulates the E95K mutation, there is a change in the potency and range of signalling. The mice have digit abnormalities consistent with the human disorder.
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This work was supported by grants from the Research Grants Council and University Grants Council of Hong Kong (N_HKU705/02, HKU2/02C and AoE/M-04/04), and The National Key Scientific Program (2007CB947300). We thank P. Tam for suggestions and comments, P. Beachy and D. Leahy for sharing unpublished data, and K. Leung for blastocyst injections.
Author Contributions The primary affiliation for J.H. is Bio-X Center, Shanghai Jiao Tong University. B.G. and J.H. designed and performed the experiments and analysed the data. K.F.L. performed the in vitro hedgehog signalling assay. F.W., S.S. and S.M. were involved in the in situ analysis of digit formation, micromass cultures and revision of the manuscript. M.C. and J.B. assisted in the chick neural tube electroporation experiments. G.M. performed the PTCH1 competitive binding assay. L.H. was involved in experimental design and manuscript revision. K.S.E.C. was involved in experimental design, generation of the BDA1 mouse, data analysis, interpretation and manuscript revision. D.C. coordinated the experimental design, analysed the data, and together with B.G. and J.H. interpreted the results and wrote the manuscript.
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Gao, B., Hu, J., Stricker, S. et al. A mutation in Ihh that causes digit abnormalities alters its signalling capacity and range. Nature 458, 1196–1200 (2009). https://doi.org/10.1038/nature07862
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