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Published online: 11 March 2009 | doi:10.1038/nchina.2009.47

Congenital disorders: Mutation fingered

Felix Cheung

Introduction

© (2009) Nature

People with brachydactyly type A1 (BDA1) are born with disproportionately short fingers or toes. This heritable trait is a classical example of 'Mendelian inheritance' — its presence is caused by mutations in a single gene. Previous studies have identified the gene responsible for this in humans as Indian hedgehog (IHH). However, the molecular basis of mutations in IHH has not been known. Danny Chan at the University of Hong Kong, Lin He at Shanghai Jiao Tong University, Fudan University and the Chinese Academy of Sciences in Shanghai, and co-workers¹ have now identified the mutation in IHH that is responsible for BDA1 and discovered the way it affects limb growth.

The human hand has five digits, each with three digital bones (phalanges). People with BDA1 are characterized by shortened or absent middle phalanges in the digits.

Like the human hand, the paw of a mouse has multiple phalanges (pictured left). The researchers found that mice carrying a BDA1 mutation, known as E95k, in their Indian hedgehog ihh had severely shortened or absent middle phalanges from embryonic day 13.5 (pictured right). The finding suggests that the E95k mutation is responsible for BDA1 in humans.

Hedgehog proteins (IHH) are important morphogens, which promote limb growth. Negative regulators, such as PTCH1 and HIP1, are thought to regulate fetal bone formation by monitoring the range and capacity of IHH signalling.

When the researchers looked into the effect of E95K on human digit development, they found that the mutation impairs the interaction of IHH with PTCH1 and HIP1. The impairment allows the IHH to diffuse further into the interzone — the site of the future joint. As a result, the middle phalange has a smaller template for development. The finding gives the first insight into the role of hedgehog mutations in the pathogenesis of BDA1.

The authors of this work are from:
Department of Biochemistry, University of Hong Kong, Hong Kong, China; Bio-X Center, Shanghai Jiao Tong University, Shanghai, China; Max-Planck Institute for Molecular Genetics, Berlin, Germany; Institut für Medizinische Genetik, Charité, Universitätsmedizin Berlin, Berlin, Germany; Centre for Reproduction, Development and Growth, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China; Institute for Chemistry and Biochemistry, Free University Berlin, Berlin, Germany; Developmental Neurobiology, National Institute for Medical Research, London, UK; Institute for Nutritional Sciences, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Shanghai, China; Institutes of Biomedical Sciences, Fudan University, Shanghai, China.

Reference

1. Gao, B. et al. A mutation in Ihh that causes digit abnormalities alters its signalling capacity and range. Nature doi:10.1038/nature07862 (2009). | Article |