A mutation in Ihh that causes digit abnormalities alters its signalling capacity and range.
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.
Gao
Bo
B
Department of Biochemistry, the University of Hong Kong, Hong Kong, China.
Hu
Jianxin
J
Stricker
Sigmar
S
Cheung
Martin
M
Ma
Gang
G
Law
Kit Fong
KF
Witte
Florian
F
Briscoe
James
J
Mundlos
Stefan
S
He
Lin
L
Cheah
Kathryn S E
KS
Chan
Danny
D
D000818:Animals; D002645:Chickens; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D053823:Hedgehog Proteins / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D017880:Limb Deformities, Congenital / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009154:Mutation / Q000235:genetics*; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
D004268:DNA-Binding Proteins; D053823:Hedgehog Proteins; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; C514061:ihh protein, mouse