title: Mutations in PATCHED-1, the receptor for SONIC HEDGEHOG, are associated with holoprosencephaly.
abstract: Holoprosencephaly (HPE) is the most commonly occurring congenital structural forebrain anomaly in humans. HPE is associated with mental retardation and craniofacial malformations. The genetic causes of HPE have recently begun to be identified, and we have previously shown that HPE can be caused by haploinsufficiency for SONIC HEDGEHOG ( SHH). We hypothesize that mutations in genes encoding other components of the SHH signaling pathway could also be associated with HPE. PATCHED-1 (PTCH), the receptor for SHH, normally acts to repress SHH signaling. This repression is relieved when SHH binds to PTCH. We analyzed PTCH as a candidate gene for HPE. Four different mutations in PTCHwere detected in five unrelated affected individuals. We predict that by enhancing the repressive activity of PTCH on the SHH pathway, these mutations cause decreased SHH signaling, and HPE results. The mutations could affect the ability of PTCH to bind SHH or perturb the intracellular interactions of PTCH with other proteins involved in SHH signaling. These findings further demonstrate the genetic heterogeneity associated with HPE, as well as showing that mutations in different components of a single signaling pathway can result in the same clinical condition.
authors.affiliation: Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Ming
authors.forename: Michelle E
authors.initials: ME
authors.lastname: Kaupas
authors.forename: Erich
authors.initials: E
authors.lastname: Roessler
authors.forename: Han G
authors.initials: HG
authors.lastname: Brunner
authors.forename: Mahin
authors.initials: M
authors.lastname: Golabi
authors.forename: Mustafa
authors.initials: M
authors.lastname: Tekin
authors.forename: Robert F
authors.initials: RF
authors.lastname: Stratton
authors.forename: Eva
authors.initials: E
authors.lastname: Sujansky
authors.forename: Sherri J
authors.initials: SJ
authors.lastname: Bale
authors.forename: Maximilian
authors.initials: M
authors.lastname: Muenke
mesh_terms: D002648:Child; D002675:Child, Preschool; D053823:Hedgehog Proteins; D016142:Holoprosencephaly / Q000235:genetics*; D006801:Humans; D007223:Infant; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface; D015534:Trans-Activators / Q000378:metabolism*
chemical_list: D053823:Hedgehog Proteins; D008565:Membrane Proteins; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface; C509239:SHH protein, human; D015534:Trans-Activators