Multi-layered mutation in hedgehog-related genes in Gorlin syndrome may affect the phenotype

• DOI: 10.1371/journal.pone.0184702
• Publication Date: 2017-09-15T13:41:01Z
• Authors: Shoko Onodera; Akiko Saito; Daigo Hasegawa; Nana Morita; Katsuhito Watanabe; Takeshi Nomura; Takahiko Shibahara; Shinsuke Ohba; Akira Yamaguchi; Toshifumi Azuma
• Keywords: PTCH1; Smoothened; GLI1

Gorlin syndrome is a genetic disorder of autosomal dominant inheritance that predisposes the affected individual to variety disorders are attributed largely heterozygous germline patched1 (PTCH1) mutations. PTCH1 hedgehog (Hh) receptor as well repressor, mutation which leads constitutive activation Hh pathway. pathway encompasses wide cellular signaling cascades, involve several molecules; however, no associated genotype-phenotype correlations have been reported. Recently, mutations in Suppressor fused homolog (SUFU) or PTCH2 were reported patients with syndrome. These facts suggest multi-layered may contribute development We demonstrated multiple Hh-related genes addition PTCH1, possibly act an additive multiplicative manner and lead High-throughput sequencing was performed analyze exome sequences four unrelated patient genomes. Mutations gene detected all patients. Specific nucleotide variations frameshift identified along inferred amino acid changes further filtered 84 different closely related signaling. Fifty three these had enough coverage over ×30. The results compared reduce number sequence variants each individuals. discovered genes, PTCH2, BOC, WNT9b, predicted functional impact assessed by MutationTaster2 PolyPhen-2 (Polymorphism Phenotyping v2) analysis. It noticeable BOC molecules. No significant observed SUFU. Multi-layered change level signals, explain phenotypic variability