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

• DOI: 10.1038/ng577
• Publication Date: 2002-07-26T08:32:48Z
• Authors: Bo Gao; Jingzhi Guo; Chaowen She; Anli Shu; Maosheng Yang; Zheng Tan; Xinping Yang; Shengzhen Guo; Guoying Feng; Lin He
• Keywords: Models, Molecular; 0301 basic medicine; Protein Structure; China; Mutation/*genetics; DNA Mutational Analysis; Molecular Sequence Data; Tertiary/genetics; Heterozygote Detection; Polymerase Chain Reaction; Congenital/*classification/epidemiology/*genetics; Protein Structure, Tertiary/genetics; 03 medical and health sciences; Models; Terminology as Topic; Humans; Dominant; Hedgehog Proteins; Amino Acid Substitution/genetics; China/epidemiology; Proteins/*genetics; Conserved Sequence; Genes, Dominant; Base Sequence; Genetic Carrier Screening; Molecular; Proteins; Hand Deformities, Congenital/*classification/epidemiology/*genetics; Hand Deformities; Pedigree; Protein Structure, Tertiary; 3. Good health; Phenotype; Genes; Amino Acid Substitution; Mutation; *Trans-Activators; Signal Transduction/genetics; Hand Deformities, Congenital; Signal Transduction

Brachydactyly type A-1 (BDA-1; MIM 112500) is characterized by shortening or missing of the middle phalanges (Fig. 1a). 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.