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The Ptch1 DL mouse: A new model to study lambdoid craniosynostosis and basal cell nevus syndrome‐associated skeletal defects
Author(s) -
Feng Weiguo,
Choi Irene,
Clouthier David E.,
Niswander Lee,
Williams Trevor
Publication year - 2013
Publication title -
genesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.093
H-Index - 110
eISSN - 1526-968X
pISSN - 1526-954X
DOI - 10.1002/dvg.22416
Subject(s) - ptch1 , biology , craniosynostosis , patched , hedgehog , skull , craniofacial , cranial vault , basal cell nevus syndrome , anatomy , genetics , pathology , medicine , basal cell carcinoma , gene , basal cell
Mouse models provide valuable opportunities for probing the underlying pathology of human birth defects. By using an N ‐ethyl‐ N ‐nitrosourea‐based screen for recessive mutations affecting craniofacial anatomy, we isolated a mouse strain, Dogface‐like ( DL ), with abnormal skull and snout morphology. Examination of the skull indicated that these mice developed craniosynostosis of the lambdoid suture. Further analysis revealed skeletal defects related to the pathology of basal cell nevus syndrome (BCNS) including defects in development of the limbs, scapula, ribcage, secondary palate, cranial base, and cranial vault. In humans, BCNS is often associated with mutations in the Hedgehog receptor PTCH1 and genetic mapping in DL identified a point mutation at a splice donor site in Ptch1 . By using genetic complementation analysis we determined that DL is a hypomorphic allele of Ptch1 , leading to increased Hedgehog signaling. Two aberrant transcripts are generated by the mutated Ptch1 DL gene, which would be predicted to reduce significantly the levels of functional Patched1 protein. This new Ptch1 allele broadens the mouse genetic reagents available to study the Hedgehog pathway and provides a valuable means to study the underlying skeletal abnormalities in BCNS. In addition, these results strengthen the connection between elevated Hedgehog signaling and craniosynostosis. genesis 51:677–689. © 2013 Wiley Periodicals, Inc.