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Mutations in IHH, encoding Indian hedgehog, cause brachydactyly type A-1

Abstract

Brachydactyly type A-1 (BDA-1; MIM 112500) is characterized by shortening or missing of the middle phalanges (Fig. 1a)1. It was first identified by Farabee in 1903 (ref. 2), is the first recorded example of a human anomaly with Mendelian autosomal-dominant inheritance and, as such, is cited in most genetic and biological textbooks. Here we show that mutations in IHH, which encodes Indian hedgehog, cause BDA-1. We have identified three heterozygous missense mutations in the region encoding the amino-terminal signaling domain in all affected members of three large, unrelated families. The three mutant amino acids, which are conserved across all vertebrates and invertebrates studied so far, are predicted to be adjacent on the surface of IHH.

a, The hands and feet of an affected individual in family III. In some affected individuals all middle phalanges are missing or fused to the distal phalanges; in others, one to three fingers or toes have missing or fused phalanges. b, Affected individual with two children (the affected child is on the right) in family III. Note short stature. c, BDA-1 pedigrees I, II and III; affected individuals are denoted by filled symbols.

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Figure 2: Structure of IHH and function of SHH.
Figure 3: Mutation analysis.
Figure 4: Three-dimensional analysis based on mouse Shh.

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Acknowledgements

We thank Shanghai Jiao Tong University, Chinese Academy of Sciences, The Chinese National Human Genome Center at Shanghai, the Science & Technology Commission of Shanghai Municipality, the National Natural Science Foundation of China, the Unilever Co. Ltd. and the National 973 projects for generous financial support.

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Correspondence to Lin He.

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Gao, B., Guo, J., She, C. et al. Mutations in IHH, encoding Indian hedgehog, cause brachydactyly type A-1. Nat Genet 28, 386–388 (2001). https://doi.org/10.1038/ng577

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