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

Brachyclactyly 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 mo st genetic and biological textbooks. Here we show that mutations in IHH, wh ich encodes Indian hedgehog, cause BDA-1. We have identified three heterozy gous missense mutations in the region encoding the amino-terminal signaling domain in all affected members of three large, unrelated families. The thr ee mutant amino acids, which are conserved across all vertebrates and inver tebrates studied so far, are predicted to be adjacent on the surface of IHH .