GLI1 inactivation is associated with developmental phenotypes overlapping with Ellis-van Creveld syndrome

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dc.authorid0000-0001-7440-0347en_US
dc.authorid0000-0002-9809-0977en_US
dc.authorid0000-0001-5832-7098en_US
dc.contributor.authorCampos, Adrian Palencia
dc.contributor.authorUllah, Asmat
dc.contributor.authorNevado, Julian
dc.contributor.authorYıldırım, Ruken
dc.contributor.authorÜnal, Edip
dc.contributor.authorCiorraga, Maria
dc.contributor.authorBarruz, Pilar
dc.contributor.authorChico, Lucia
dc.date.accessioned2024-03-25T10:31:01Z
dc.date.available2024-03-25T10:31:01Z
dc.date.issued2017en_US
dc.departmentDicle Üniversitesi, Tıp Fakültesi, Dahili Tıp Bilimleri Bölümü, Çocuk Sağlığı ve Hastalıkları Ana Bilim Dalıen_US
dc.description.abstractGLI1, GLI2 and GLI3 form a family of transcription factors which regulate development by mediating the action of Hedgehog (Hh) morphogens. Accordingly, inactivating variants in GLI2 and GLI3 are found in several developmental disorders. In contrast, loss-of-function mutations in GLI1 have remained elusive, maintaining enigmatic the role of this gene in the human embryo. We describe eight patients from three independent families having biallelic truncating variants in GLI1 and developmental defects overlapping with Ellis-van Creveld syndrome (EvC), a disease caused by diminished Hh signaling. Two families had mutations in the last exon of the gene and a third family was identified with an N-terminal stop gain variant predicted to be degraded by the NMD-pathway. Analysis of fibroblasts from one of the patients with homozygous C-terminal truncation of GLI1 demonstrated that the corresponding mutant GLI1 protein is fabricated by patient cells and becomes upregulated in response to Hh signaling. However, the transcriptional activity of the truncated GLI1 factor was found to be severely impaired by cell culture and in vivo assays, indicating that the balance between GLI repressors and activators is altered in affected subjects. Consistent with this, reduced expression of the GLI target PTCH1 was observed in patient fibroblasts after chemical induction of the Hh pathway.We conclude that GLI1 inactivation is associated with a phenotypic spectrum extending from isolated postaxial polydactyly to an EvC-like condition.en_US
dc.identifier.citationCampos, A. P., Ullah, A., Nevado, J., Yıldırım, R., Ünal, E., Ciorraga, M. ve diğerleri. (2017). GLI1 inactivation is associated with developmental phenotypes overlapping with Ellis-van Creveld syndrome. Human Molecular Genetics, 26(23), 4556-4571.en_US
dc.identifier.doi10.1093/hmg/ddx335
dc.identifier.endpage4571en_US
dc.identifier.issn0964-6906
dc.identifier.issue23en_US
dc.identifier.pmid28973407
dc.identifier.scopus2-s2.0-85042217949
dc.identifier.scopusqualityQ2
dc.identifier.startpage4556en_US
dc.identifier.urihttps://hdl.handle.net/11468/13702
dc.identifier.volume26en_US
dc.identifier.wosWOS:000416662700002
dc.identifier.wosqualityQ1
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.institutionauthorÜnal, Edip
dc.language.isoenen_US
dc.publisherOxford University Pressen_US
dc.relation.ispartofHuman Molecular Genetics
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectEllis-van Creveld syndromeen_US
dc.subjectGLI1 inactivationen_US
dc.titleGLI1 inactivation is associated with developmental phenotypes overlapping with Ellis-van Creveld syndromeen_US
dc.titleGLI1 inactivation is associated with developmental phenotypes overlapping with Ellis-van Creveld syndrome
dc.typeArticleen_US

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