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Deregulated FGF and homeotic gene expression underlies cerebellar vermis hypoplasia in CHARGE syndrome.
- Source :
-
ELife [Elife] 2013 Dec 24; Vol. 2, pp. e01305. Date of Electronic Publication: 2013 Dec 24. - Publication Year :
- 2013
-
Abstract
- Mutations in CHD7 are the major cause of CHARGE syndrome, an autosomal dominant disorder with an estimated prevalence of 1/15,000. We have little understanding of the disruptions in the developmental programme that underpin brain defects associated with this syndrome. Using mouse models, we show that Chd7 haploinsufficiency results in reduced Fgf8 expression in the isthmus organiser (IsO), an embryonic signalling centre that directs early cerebellar development. Consistent with this observation, Chd7 and Fgf8 loss-of-function alleles interact during cerebellar development. CHD7 associates with Otx2 and Gbx2 regulatory elements and altered expression of these homeobox genes implicates CHD7 in the maintenance of cerebellar identity during embryogenesis. Finally, we report cerebellar vermis hypoplasia in 35% of CHARGE syndrome patients with a proven CHD7 mutation. These observations provide key insights into the molecular aetiology of cerebellar defects in CHARGE syndrome and link reduced FGF signalling to cerebellar vermis hypoplasia in a human syndrome. DOI: http://dx.doi.org/10.7554/eLife.01305.001.
- Subjects :
- Animals
CHARGE Syndrome genetics
CHARGE Syndrome pathology
Cerebellar Vermis abnormalities
DNA Helicases genetics
DNA Helicases metabolism
DNA-Binding Proteins deficiency
DNA-Binding Proteins genetics
DNA-Binding Proteins metabolism
Disease Models, Animal
Fibroblast Growth Factor 8 deficiency
Fibroblast Growth Factor 8 genetics
Gene Expression Regulation
Genotype
Haploinsufficiency
Homeodomain Proteins genetics
Humans
Magnetic Resonance Imaging
Mice, Inbred C57BL
Mice, Inbred DBA
Mice, Knockout
Mutation
Otx Transcription Factors genetics
Phenotype
CHARGE Syndrome metabolism
Cerebellar Vermis metabolism
Fibroblast Growth Factor 8 metabolism
Homeodomain Proteins metabolism
Otx Transcription Factors metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2050-084X
- Volume :
- 2
- Database :
- MEDLINE
- Journal :
- ELife
- Publication Type :
- Academic Journal
- Accession number :
- 24368733
- Full Text :
- https://doi.org/10.7554/eLife.01305