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Abstract:

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.

Registro:

Documento: Artículo
Título:Mutations in CDON, encoding a hedgehog receptor, result in holoprosencephaly and defective interactions with other hedgehog receptors
Autor:Bae, G.-U.; Domené, S.; Roessler, E.; Schachter, K.; Kang, J.-S.; Muenke, M.; Krauss, R.S.
Filiación:Department of Developmental and Regenerative Biology, Mount Sinai School of Medicine, New York, NY 10029, United States
Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon 440-746, South Korea
Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, United States
College of Pharmacy, Sookmyung Women's University, Seoul 140-742, South Korea
Ingebi-Conicet, Vuelta de Obligado 2490, Buenos Aires 1428, Argentina
Stem Cell Center, Department of Laboratory Medicine, Lund University, Lund 22184, Sweden
Palabras clave: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
Año:2011
Volumen:89
Número:2
Página de inicio:231
Página de fin:240
DOI: http://dx.doi.org/10.1016/j.ajhg.2011.07.001
Título revista:American Journal of Human Genetics
Título revista abreviado:Am. J. Hum. Genet.
ISSN:00029297
CODEN:AJHGA
CAS:CDON protein, human; Cdo protein, mouse; Cell Adhesion Molecules; Cell Cycle Proteins; GAS1 protein, human; GPI-Linked Proteins; Hedgehog Proteins; Receptors, Cell Surface; Tumor Suppressor Proteins
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00029297_v89_n2_p231_Bae

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Citas:

---------- APA ----------
Bae, G.-U., Domené, S., Roessler, E., Schachter, K., Kang, J.-S., Muenke, M. & Krauss, R.S. (2011) . Mutations in CDON, encoding a hedgehog receptor, result in holoprosencephaly and defective interactions with other hedgehog receptors. American Journal of Human Genetics, 89(2), 231-240.
http://dx.doi.org/10.1016/j.ajhg.2011.07.001
---------- CHICAGO ----------
Bae, G.-U., Domené, S., Roessler, E., Schachter, K., Kang, J.-S., Muenke, M., et al. "Mutations in CDON, encoding a hedgehog receptor, result in holoprosencephaly and defective interactions with other hedgehog receptors" . American Journal of Human Genetics 89, no. 2 (2011) : 231-240.
http://dx.doi.org/10.1016/j.ajhg.2011.07.001
---------- MLA ----------
Bae, G.-U., Domené, S., Roessler, E., Schachter, K., Kang, J.-S., Muenke, M., et al. "Mutations in CDON, encoding a hedgehog receptor, result in holoprosencephaly and defective interactions with other hedgehog receptors" . American Journal of Human Genetics, vol. 89, no. 2, 2011, pp. 231-240.
http://dx.doi.org/10.1016/j.ajhg.2011.07.001
---------- VANCOUVER ----------
Bae, G.-U., Domené, S., Roessler, E., Schachter, K., Kang, J.-S., Muenke, M., et al. Mutations in CDON, encoding a hedgehog receptor, result in holoprosencephaly and defective interactions with other hedgehog receptors. Am. J. Hum. Genet. 2011;89(2):231-240.
http://dx.doi.org/10.1016/j.ajhg.2011.07.001