Human Genetics

, Volume 110, Issue 4, pp 297–301

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
Original Investigation

DOI: 10.1007/s00439-002-0695-5

Cite this article as:
Ming, J.E., Kaupas, M.E., Roessler, E. et al. Hum Genet (2002) 110: 297. doi:10.1007/s00439-002-0695-5

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.

Copyright information

© Springer-Verlag 2002

Authors and Affiliations

  • Jeffrey E. Ming
    • 1
  • Michelle E. Kaupas
    • 2
  • Erich Roessler
    • 3
  • Han G. Brunner
    • 4
  • Mahin Golabi
    • 5
  • Mustafa Tekin
    • 6
  • Robert F. Stratton
    • 7
  • Eva Sujansky
    • 8
  • Sherri J. Bale
    • 9
  • Maximilian Muenke
    • 1
  1. 1.Division of Human Genetics, Departments of Pediatrics and Genetics, Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PennsylvaniaUSA
  2. 2.Division of Neurology, Departments of Pediatrics and Genetics, Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PennsylvaniaUSA
  3. 3.Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, 10 Center Drive, MSC 1852, Building 10, 10C103, Bethesda, MD 20892-1852USA
  4. 4.University of Nijmegen, NijmegenThe Netherlands
  5. 5.University of California, San Francisco, CaliforniaUSA
  6. 6.Medical College of Virginia, Richmond, VirginiaUSA
  7. 7.University of Texas Health Science Center, San Antonio, TexasUSA
  8. 8.Children’s Hospital, Denver, ColoradoUSA
  9. 9.NIAMS, NIH, Bethesda, MarylandUSA