2. Academic Validation
  3. GLI1 inactivation is associated with developmental phenotypes overlapping with Ellis-van Creveld syndrome

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

  • Hum Mol Genet. 2017 Dec 1;26(23):4556-4571. doi: 10.1093/hmg/ddx335.
Adrian Palencia-Campos 1 2,  Asmat Ullah 3,  Julian Nevado 4,  Ruken Yildirim 5,  Edip Unal 6,  Maria Ciorraga 7,  Pilar Barruz 4,  Lucia Chico 1,  Francesca Piceci-Sparascio 8,  Valentina Guida 8,  Alessandro De Luca 8,  Hülya Kayserili 9,  Irfan Ullah 3,  Margit Burmeister 10 11,  Pablo Lapunzina 2 4,  Wasim Ahmad 3,  Aixa V Morales 7,  Victor L Ruiz-Perez 1 2 4
Affiliations

Affiliations

  • 1 Instituto de Investigaciones Biomédicas 'Alberto Sols', CSIC-UAM, 28029 Madrid, Spain.
  • 2 CIBER de Enfermedades Raras (CIBERER), ISCIII, Spain.
  • 3 Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
  • 4 Instituto de Genética Médica y Molecular (INGEMM), Hospital Universitario La Paz-IdiPaz-UAM, 28046 Madrid, Spain.
  • 5 Diyarbakir Children State Hospital, Clinic of Pediatric Endocrinology, Diyarbakir, Turkey.
  • 6 Department of Pediatric Endocrinology, Dicle University, Diyarbakir, Turkey.
  • 7 Department of Cellular, Molecular and Developmental Neurobiology, Instituto Cajal, CSIC, 28002 Madrid, Spain.
  • 8 Molecular Genetics Unit, Casa Sollievo della Sofferenza Hospital, IRCCS, 71013 San Giovanni Rotondo, Italy.
  • 9 Medical Genetics Department, Koç University School of Medicine (KUSoM) Istanbul, Istanbul 34010, Turkey.
  • 10 Department of Psychiatry.
  • 11 Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.
PMID: 28973407 DOI: 10.1093/hmg/ddx335
Abstract

GLI1, 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.

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