A Mutation in Ihh That Causes Digit Abnormalities Alters Its Signalling Capacity and Range

Overview

Journal Nature

Specialty Science

Date 2009 Mar 3

PMID 19252479

Citations 46

Authors

Bo Gao

Jianxin Hu

Sigmar Stricker

Martin Cheung

Gang Ma

Kit Fong Law

Florian Witte

James Briscoe

Stefan Mundlos

Lin He

Kathryn S E Cheah

Danny Chan

Affiliations

Soon will be listed here.

Abstract

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). Hedgehog proteins are important morphogens for a wide range of developmental processes. 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 partners. 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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