Gorlin syndrome-induced pluripotent stem cells form medulloblastoma with loss of heterozygosity in PTCH1.

Yu Ikemoto,Toshino Motojima,Ibuki Kokido,Katsunori Fujii,Akihiro Umezawa,Kazuhiro Kajiwara,Masashi Toyoda,Toshiyuki Miyashita,Michiyo Nasu,Hiromi Hatsuse

doi:10.18632/aging.103258

Abstract

Gorlin syndrome is a rare autosomal dominant hereditary disease with a high incidence of tumors such as basal cell carcinoma and medulloblastoma. Disease-specific induced pluripotent stem cells (iPSCs) and an animal model have been used to analyze disease pathogenesis. In this study, we generated iPSCs derived from fibroblasts of four patients with Gorlin syndrome (Gln-iPSCs) with heterozygous mutations of the PTCH1 gene. Gln-iPSCs from the four patients developed into medulloblastoma, a manifestation of Gorlin syndrome, in 100% (four out of four), of teratomas after implantation into immunodeficient mice, but none (0/584) of the other iPSC-teratomas did so. One of the medulloblastomas showed loss of heterozygosity in the PTCH1 gene while the benign teratoma, i.e. the non-medulloblastoma portion, did not, indicating a close clinical correlation between tumorigenesis in Gorlin syndrome patients and Gln-iPSCs.

Highlights

Gorlin syndrome, a rare autosomal dominant disorder, is characterized by developmental defects in multiple organs or tissues such as the skin, nervous system, eyes, endocrine systems and bones
We generated induced pluripotent stem cells (iPSCs) from human cells with mutations in the PTCH1 gene by Sendai virus infection-mediated expression of OCT4/3, SOX2, KLF4, and c-MYC
When the reprogramming factors OCT4/3, SOX2, KLF4 and c-MYC were introduced into 4.0 x cells, iPSCs generated from four patients with

Summary

Introduction

A rare autosomal dominant disorder, is characterized by developmental defects in multiple organs or tissues such as the skin (palmar or plantar pits), nervous system, eyes, endocrine systems and bones (bifid ribs). Gorlin syndrome is associated with tumorigenesis such as development of basal cell carcinoma (BCC), medulloblastoma or keratocystic odontogenic tumor. Gorlin syndrome is caused by mutations in the PTCH1 gene, a human homologue of Drosophila patched. Hedgehog signaling regulates cell growth and development, and the disorder of this pathway gives rise to developmental anomalies and diverse tumors such www.aging-us.com as those seen in Gorlin syndrome [1]. Aberrant activation of hedgehog signaling causes basal cell carcinoma [2, 3] and medulloblastoma [4, 5]

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Conclusion