A novel truncating variant of GLI2 associated with Culler-Jones syndrome impairs Hedgehog signalling

Fabiola Valenza, Davide Cittaro, Elia Stupka, Donatella Biancolini, Maria Grazia Patricelli, Dario Bonanomi, Dejan Lazarević

Research output: Contribution to journalArticlepeer-review


Background GLI2 encodes for a transcription factor that controls the expression of several genes in the Hedgehog pathway. Mutations in GLI2 have been described as causative of a spectrum of clinical phenotypes, notably holoprosencephaly, hypopituitarism and postaxial polydactyl. Methods In order to identify causative genetic variant, we performed exome sequencing of a trio from an Italian family with multiple affected individuals presenting clinical phenotypes in the Culler-Jones syndrome spectrum. We performed a series of cell-based assays to test the functional properties of mutant GLI2. Results Here we report a novel deletion c.3493delC (p.P1167LfsX52) in the C-terminal activation domain of GLI2. Functional assays confirmed the pathogenicity of the identified variant and revealed a dominant-negative effect of mutant GLI2 on Hedgehog signalling. Conclusions Our results highlight the variable clinical manifestation of GLI2 mutations and emphasize the value of functional characterisation of novel gene variants to assist genetic counselling and diagnosis.

Original languageEnglish
Article numbere0210097
JournalPLoS One
Issue number1
Publication statusPublished - Jan 2019

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General


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