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Multiple enhancers located in a 1-Mb region upstream of POU3F4 promote expression during inner ear development and may be required for hearing.
- Source :
-
Human genetics [Hum Genet] 2010 Oct; Vol. 128 (4), pp. 411-9. Date of Electronic Publication: 2010 Jul 29. - Publication Year :
- 2010
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Abstract
- POU3F4 encodes a POU-domain transcription factor required for inner ear development. Defects in POU3F4 function are associated with X-linked deafness type 3 (DFN3). Multiple deletions affecting up to ~900-kb upstream of POU3F4 are found in DFN3 patients, suggesting the presence of essential POU3F4 enhancers in this region. Recently, an inner ear enhancer was reported that is absent in most DFN3 patients with upstream deletions. However, two indications suggest that additional enhancers in the POU3F4 upstream region are required for POU3F4 function during inner ear development. First, there is at least one DFN3 deletion that does not eliminate the reported enhancer. Second, the expression pattern driven by this enhancer does not fully recapitulate Pou3f4 expression in the inner ear. Here, we screened a 1-Mb region upstream of the POU3F4 gene for additional cis-regulatory elements and searched for novel DFN3 mutations in the identified POU3F4 enhancers. We found several novel enhancers for otic vesicle expression. Some of these also drive expression in kidney, pancreas and brain, tissues that are known to express Pou3f4. In addition, we report a new and smallest deletion identified so far in a DFN3 family which eliminates 3.9 kb, comprising almost exclusively the previous reported inner ear enhancer. We suggest that multiple enhancers control the expression of Pou3f4 in the inner ear and these may contribute to the phenotype observed in DFN3 patients. In addition, the novel deletion demonstrates that the previous reported enhancer, although not sufficient, is essential for POU3F4 function during inner ear development.
- Subjects :
- Animals
Base Sequence
DNA Mutational Analysis
Ear, Inner growth & development
Embryo, Nonmammalian embryology
Embryo, Nonmammalian metabolism
Family Health
Female
Gene Deletion
Gene Expression Regulation, Developmental
Green Fluorescent Proteins genetics
Green Fluorescent Proteins metabolism
Hearing Loss genetics
Humans
In Situ Hybridization
Male
Microscopy, Fluorescence
Pedigree
Recombinant Fusion Proteins genetics
Recombinant Fusion Proteins metabolism
Regulatory Sequences, Nucleic Acid genetics
Xenopus embryology
Xenopus genetics
5' Flanking Region genetics
Ear, Inner metabolism
Enhancer Elements, Genetic genetics
Hearing genetics
POU Domain Factors genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1432-1203
- Volume :
- 128
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Human genetics
- Publication Type :
- Academic Journal
- Accession number :
- 20668882
- Full Text :
- https://doi.org/10.1007/s00439-010-0864-x