FunctionIntercellular signal essential for a variety of patterning events during development. Binds to the patched (PTC) receptor, which functions in association with smoothened (SMO), to activate the transcription of target genes. Implicated in endochondral ossification: may regulate the balance between growth and ossification of the developing bones. Induces the expression of parathyroid hormone-related protein (PTHRP).
Tissue specificityExpressed in embryonic lung, and in adult kidney and liver.
Involvement in diseaseDefects in IHH are the cause of brachydactyly type A1 (BDA1) [MIM:112500]. BDA1 is an autosomal dominant disorder characterized by middle phalanges of all the digits rudimentary or fused with the terminal phalanges. The proximal phalanges of the thumbs and big toes are short. Defects in IHH are a cause of acrocapitofemoral dysplasia (ACFD) [MIM:607778]. ACFD is a disorder characterized by short stature of variable severity with postnatal onset. The most constant radiographic abnormalities are observed in the tubular bones of the hands and in the proximal part of the femur. Cone-shaped epiphyses or a similar epiphyseal configuration with premature epimetaphyseal fusion result in shortening of the skeletal components involved. Cone-shaped epiphyses were also present to a variable extent at the shoulders, knees, and ankles.
Sequence similaritiesBelongs to the hedgehog family.
Post-translational modificationsThe C-terminal domain displays an autoproteolysis activity and a cholesterol transferase activity. Both activities result in the cleavage of the full-length protein and covalent attachment of a cholesterol moiety to the C-terminal of the newly generated N-terminal fragment (N-product). The N-product is the active species in both local and long-range signaling, whereas the C-product has no signaling activity. Cholesterylation is required for N-product targeting to lipid rafts and multimerization. Palmitoylated. N-palmitoylation is required for N-product multimerization and full activity.
Cellular localizationSecreted > extracellular space. The C-terminal peptide diffuses from the cell and Cell membrane. The N-terminal peptide remains associated with the cell surface.