Mutations in PATCHED-1, the receptor for SONIC HEDGEHOG, are associated with holoprosencephaly

Jeffrey E. Ming, Michelle E. Kaupas, Erich Roessler, Han G. Brunner, Mahin Golabi, Mustafa Tekin, Robert F. Stratton, Eva Sujansky, Sherri J. Bale, Maximilian Muenke

Research output: Contribution to journalArticle

174 Citations (Scopus)

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 PTCH were 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.

Original languageEnglish
Pages (from-to)297-301
Number of pages5
JournalHuman Genetics
Volume110
Issue number4
DOIs
StatePublished - Apr 1 2002
Externally publishedYes

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Holoprosencephaly
Mutation
Haploinsufficiency
Aptitude
Genetic Heterogeneity
Prosencephalon
Intellectual Disability
Genes

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Ming, J. E., Kaupas, M. E., Roessler, E., Brunner, H. G., Golabi, M., Tekin, M., ... Muenke, M. (2002). Mutations in PATCHED-1, the receptor for SONIC HEDGEHOG, are associated with holoprosencephaly. Human Genetics, 110(4), 297-301. https://doi.org/10.1007/s00439-002-0695-5

Mutations in PATCHED-1, the receptor for SONIC HEDGEHOG, are associated with holoprosencephaly. / Ming, Jeffrey E.; Kaupas, Michelle E.; Roessler, Erich; Brunner, Han G.; Golabi, Mahin; Tekin, Mustafa; Stratton, Robert F.; Sujansky, Eva; Bale, Sherri J.; Muenke, Maximilian.

In: Human Genetics, Vol. 110, No. 4, 01.04.2002, p. 297-301.

Research output: Contribution to journalArticle

Ming, JE, Kaupas, ME, Roessler, E, Brunner, HG, Golabi, M, Tekin, M, Stratton, RF, Sujansky, E, Bale, SJ & Muenke, M 2002, 'Mutations in PATCHED-1, the receptor for SONIC HEDGEHOG, are associated with holoprosencephaly', Human Genetics, vol. 110, no. 4, pp. 297-301. https://doi.org/10.1007/s00439-002-0695-5
Ming, Jeffrey E. ; Kaupas, Michelle E. ; Roessler, Erich ; Brunner, Han G. ; Golabi, Mahin ; Tekin, Mustafa ; Stratton, Robert F. ; Sujansky, Eva ; Bale, Sherri J. ; Muenke, Maximilian. / Mutations in PATCHED-1, the receptor for SONIC HEDGEHOG, are associated with holoprosencephaly. In: Human Genetics. 2002 ; Vol. 110, No. 4. pp. 297-301.
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