A novel truncating variant of GLI2 associated with Culler-Jones syndrome impairs Hedgehog signalling.
Animals
Child
Craniofacial Abnormalities
/ genetics
Female
Fingers
/ abnormalities
Frameshift Mutation
HEK293 Cells
Hedgehog Proteins
/ metabolism
Human Growth Hormone
/ deficiency
Humans
Hypopituitarism
/ congenital
Male
Mice
NIH 3T3 Cells
Nuclear Proteins
/ genetics
Pedigree
Pituitary Gland, Anterior
/ abnormalities
Polydactyly
/ genetics
Signal Transduction
/ genetics
Syndrome
Toes
/ abnormalities
Zinc Finger Protein Gli2
/ genetics
Journal
PloS one
ISSN: 1932-6203
Titre abrégé: PLoS One
Pays: United States
ID NLM: 101285081
Informations de publication
Date de publication:
2019
2019
Historique:
received:
12
07
2018
accepted:
16
12
2018
entrez:
11
1
2019
pubmed:
11
1
2019
medline:
1
10
2019
Statut:
epublish
Résumé
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. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 30629636
doi: 10.1371/journal.pone.0210097
pii: PONE-D-18-20709
pmc: PMC6328167
doi:
Substances chimiques
GLI2 protein, human
0
Hedgehog Proteins
0
Nuclear Proteins
0
Zinc Finger Protein Gli2
0
Human Growth Hormone
12629-01-5
Types de publication
Case Reports
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0210097Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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