Evidence that haploinsufficiency of Ptch leads to medulloblastoma in mice

Genes Chromosomes Cancer. 2000 May;28(1):77-81.


The PTCH gene encodes a putative tumor suppressor protein; germline alterations in PTCH have been found in patients with the nevoid basal cell carcinoma syndrome (NBCCS). Medulloblastoma, a brain tumor, develops in about 3% of NBCCS patients, and mutations in PTCH have also been described in a subset of sporadic medulloblastomas. The search for the causes of medulloblastoma has been hindered by the lack of an appropriate model system for this tumor type. Recently, a transgenic mouse hemizygous for the Ptch gene was generated by homologous recombination. Medulloblastomas were found in about 19% of these mice within the first 25 weeks after birth. The status of the wild-type PTCH allele in these tumors has not been investigated. For clearer definition of the role of PTCH as a tumor suppressor in medulloblastoma, 13 cerebellar tumors from transgenic Ptch(+/-) mice were examined for alterations in the remaining Ptch allele. A single mutation was found in one tumor, a C-to-A substitution changing a tyrosine to a stop codon; all other tumors exhibited a wild-type sequence. Two tumors with normal Ptch cDNA were examined by in situ hybridization. Ptch cDNA was found in tumor cells but not in associated tumor stroma. We also examined the mRNA expression levels for the remaining Ptch allele, as well as for Gli1, a gene known to be transcriptionally activated by Ptch inactivation. Blot analysis of RNA from the 13 tumors shows that Ptch mRNA of appropriate size is expressed in all tumors at varying levels. Expression of Gli1 was increased in tumors compared to normal cerebellum. These results suggest that deletion of one copy of Ptch may be sufficient to promote medulloblastoma development in mice.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alleles
  • Animals
  • Cerebellar Neoplasms / genetics*
  • Gene Expression Regulation, Neoplastic*
  • Genes, Tumor Suppressor / genetics
  • Haplotypes / genetics*
  • Intracellular Signaling Peptides and Proteins
  • Medulloblastoma / genetics*
  • Membrane Proteins / biosynthesis
  • Membrane Proteins / genetics*
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Mutation
  • Oncogene Proteins / genetics
  • Patched Receptors
  • Patched-1 Receptor
  • RNA, Messenger / biosynthesis
  • Receptors, Cell Surface
  • Trans-Activators
  • Transcription Factors / genetics
  • Zinc Finger Protein GLI1


  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Oncogene Proteins
  • Patched Receptors
  • Patched-1 Receptor
  • Ptch1 protein, mouse
  • RNA, Messenger
  • Receptors, Cell Surface
  • Trans-Activators
  • Transcription Factors
  • Zinc Finger Protein GLI1