Abstract
Background information:
The BOR (branchio-oto-renal) syndrome is a dominant disorder most commonly caused by mutations in the EYA1 (Eyes Absent 1) gene. Symptoms commonly include deafness and renal anomalies.
Results:
We have used the embryos of the frog Xenopus laevis as an animal model for early ear development to examine the effects of different EYA1 mutations. Four eya1 mRNAs encoding proteins correlated with congenital anomalies in human were injected into early stage embryos. We show that the expression of mutations associated with BOR, even in the presence of normal levels of endogenous eya1 mRNA, leads to morphologically abnormal ear development as measured by overall otic vesicle size, establishment of sensory tissue and otic innervation. The molecular consequences of mutant eya1 expression were assessed by QPCR (quantitative PCR) analysis and in situ hybridization. Embryos expressing mutant eya1 showed altered levels of multiple genes (six1, dach, neuroD, ngnr-1 and nt3) important for normal ear development.
Conclusions:
These studies lend support to the hypothesis that dominant-negative effects of EYA1 mutations may have a role in the pathogenesis of BOR.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Amino Acid Sequence
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Animals
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Basic Helix-Loop-Helix Transcription Factors / metabolism
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Branchio-Oto-Renal Syndrome / genetics*
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Branchio-Oto-Renal Syndrome / pathology
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Branchio-Oto-Renal Syndrome / physiopathology
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Disease Models, Animal
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Ear* / abnormalities
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Ear* / embryology
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Embryo, Nonmammalian / abnormalities
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Embryo, Nonmammalian / anatomy & histology
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Embryo, Nonmammalian / metabolism
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Eye Proteins / genetics
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Eye Proteins / metabolism
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Gene Expression Regulation, Developmental
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism
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Humans
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Intracellular Signaling Peptides and Proteins* / genetics
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Intracellular Signaling Peptides and Proteins* / metabolism
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Molecular Sequence Data
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Mutation*
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism
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Nuclear Proteins* / genetics
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Nuclear Proteins* / metabolism
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Protein Tyrosine Phosphatases* / genetics
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Protein Tyrosine Phosphatases* / metabolism
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Sequence Alignment
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Xenopus Proteins* / genetics
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Xenopus Proteins* / metabolism
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Xenopus laevis* / abnormalities
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Xenopus laevis* / anatomy & histology
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Xenopus laevis* / embryology
Substances
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Basic Helix-Loop-Helix Transcription Factors
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Eye Proteins
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Homeodomain Proteins
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Intracellular Signaling Peptides and Proteins
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Nerve Tissue Proteins
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Nuclear Proteins
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RNA, Messenger
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Six1 protein, Xenopus
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Transcription Factors
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Xenopus Proteins
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Neurogenic differentiation factor 1
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Eya1 protein, Xenopus
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Protein Tyrosine Phosphatases