Mutations in CDON, encoding a hedgehog receptor, result in holoprosencephaly and defective interactions with other hedgehog receptors
Holoprosencephaly (HPE), a common human congenital anomaly defined by a failure to delineate the midline of the forebrain and/or midface, is associated with diminished Sonic hedgehog (SHH)-pathway activity in development of these structures. SHH signaling is regulated by a network of ligand-binding...
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| Acceso en línea: | http://hdl.handle.net/20.500.12110/paper_00029297_v89_n2_p231_Bae |
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todo:paper_00029297_v89_n2_p231_Bae2023-10-03T13:54:44Z Mutations in CDON, encoding a hedgehog receptor, result in holoprosencephaly and defective interactions with other hedgehog receptors Bae, G.-U. Domené, S. Roessler, E. Schachter, K. Kang, J.-S. Muenke, M. Krauss, R.S. protein Patched 1 sonic hedgehog protein animal cell article CDON gene embryo gene gene expression holoprosencephaly human missense mutation mouse nonhuman nucleotide sequence priority journal Animals Cell Adhesion Molecules Cell Cycle Proteins Cell Line Gene Expression Regulation GPI-Linked Proteins Hedgehog Proteins Holoprosencephaly Humans Mice Mutation Protein Binding Receptors, Cell Surface Repetitive Sequences, Amino Acid Tumor Suppressor Proteins Erinaceidae Holoprosencephaly (HPE), a common human congenital anomaly defined by a failure to delineate the midline of the forebrain and/or midface, is associated with diminished Sonic hedgehog (SHH)-pathway activity in development of these structures. SHH signaling is regulated by a network of ligand-binding factors, including the primary receptor PTCH1 and the putative coreceptors, CDON (also called CDO), BOC, and GAS1. Although binding of SHH to these receptors promotes pathway activity, it is not known whether interactions between these receptors are important. We report here identification of missense CDON mutations in human HPE. These mutations diminish CDON's ability to support SHH-dependent gene expression in cell-based signaling assays. The mutations occur outside the SHH-binding domain of CDON, and the encoded variant CDON proteins do not display defects in binding to SHH. In contrast, wild-type CDON associates with PTCH1 and GAS1, but the variants do so inefficiently, in a manner that parallels their activity in cell-based assays. Our findings argue that CDON must associate with both ligand and other hedgehog-receptor components, particularly PTCH1, for signaling to occur and that disruption of the latter interactions is a mechanism of HPE. © 2011 The American Society of Human Genetics. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_00029297_v89_n2_p231_Bae |
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Universidad de Buenos Aires |
| institution_str |
I-28 |
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R-134 |
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Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
protein Patched 1 sonic hedgehog protein animal cell article CDON gene embryo gene gene expression holoprosencephaly human missense mutation mouse nonhuman nucleotide sequence priority journal Animals Cell Adhesion Molecules Cell Cycle Proteins Cell Line Gene Expression Regulation GPI-Linked Proteins Hedgehog Proteins Holoprosencephaly Humans Mice Mutation Protein Binding Receptors, Cell Surface Repetitive Sequences, Amino Acid Tumor Suppressor Proteins Erinaceidae |
| spellingShingle |
protein Patched 1 sonic hedgehog protein animal cell article CDON gene embryo gene gene expression holoprosencephaly human missense mutation mouse nonhuman nucleotide sequence priority journal Animals Cell Adhesion Molecules Cell Cycle Proteins Cell Line Gene Expression Regulation GPI-Linked Proteins Hedgehog Proteins Holoprosencephaly Humans Mice Mutation Protein Binding Receptors, Cell Surface Repetitive Sequences, Amino Acid Tumor Suppressor Proteins Erinaceidae Bae, G.-U. Domené, S. Roessler, E. Schachter, K. Kang, J.-S. Muenke, M. Krauss, R.S. Mutations in CDON, encoding a hedgehog receptor, result in holoprosencephaly and defective interactions with other hedgehog receptors |
| topic_facet |
protein Patched 1 sonic hedgehog protein animal cell article CDON gene embryo gene gene expression holoprosencephaly human missense mutation mouse nonhuman nucleotide sequence priority journal Animals Cell Adhesion Molecules Cell Cycle Proteins Cell Line Gene Expression Regulation GPI-Linked Proteins Hedgehog Proteins Holoprosencephaly Humans Mice Mutation Protein Binding Receptors, Cell Surface Repetitive Sequences, Amino Acid Tumor Suppressor Proteins Erinaceidae |
| description |
Holoprosencephaly (HPE), a common human congenital anomaly defined by a failure to delineate the midline of the forebrain and/or midface, is associated with diminished Sonic hedgehog (SHH)-pathway activity in development of these structures. SHH signaling is regulated by a network of ligand-binding factors, including the primary receptor PTCH1 and the putative coreceptors, CDON (also called CDO), BOC, and GAS1. Although binding of SHH to these receptors promotes pathway activity, it is not known whether interactions between these receptors are important. We report here identification of missense CDON mutations in human HPE. These mutations diminish CDON's ability to support SHH-dependent gene expression in cell-based signaling assays. The mutations occur outside the SHH-binding domain of CDON, and the encoded variant CDON proteins do not display defects in binding to SHH. In contrast, wild-type CDON associates with PTCH1 and GAS1, but the variants do so inefficiently, in a manner that parallels their activity in cell-based assays. Our findings argue that CDON must associate with both ligand and other hedgehog-receptor components, particularly PTCH1, for signaling to occur and that disruption of the latter interactions is a mechanism of HPE. © 2011 The American Society of Human Genetics. |
| format |
JOUR |
| author |
Bae, G.-U. Domené, S. Roessler, E. Schachter, K. Kang, J.-S. Muenke, M. Krauss, R.S. |
| author_facet |
Bae, G.-U. Domené, S. Roessler, E. Schachter, K. Kang, J.-S. Muenke, M. Krauss, R.S. |
| author_sort |
Bae, G.-U. |
| title |
Mutations in CDON, encoding a hedgehog receptor, result in holoprosencephaly and defective interactions with other hedgehog receptors |
| title_short |
Mutations in CDON, encoding a hedgehog receptor, result in holoprosencephaly and defective interactions with other hedgehog receptors |
| title_full |
Mutations in CDON, encoding a hedgehog receptor, result in holoprosencephaly and defective interactions with other hedgehog receptors |
| title_fullStr |
Mutations in CDON, encoding a hedgehog receptor, result in holoprosencephaly and defective interactions with other hedgehog receptors |
| title_full_unstemmed |
Mutations in CDON, encoding a hedgehog receptor, result in holoprosencephaly and defective interactions with other hedgehog receptors |
| title_sort |
mutations in cdon, encoding a hedgehog receptor, result in holoprosencephaly and defective interactions with other hedgehog receptors |
| url |
http://hdl.handle.net/20.500.12110/paper_00029297_v89_n2_p231_Bae |
| work_keys_str_mv |
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| _version_ |
1807317110807855104 |