title: Molecular effects of Eya1 domain mutations causing organ defects in BOR syndrome.
abstract: Eya1 is a critical gene for mammalian organogenesis. Mutations in human EYA1 cause branchio-oto-renal (BOR) syndrome, an autosomal dominant disorder characterized by varying combinations of branchial, otic and renal anomalies, whereas deletion of mouse Eya1 results in the absence of multiple organ formation. Eya1 and other Eya gene products share a highly conserved 271 amino acid Eya domain that is required for protein-protein interaction. Recently, several point mutations that result in single amino acid substitutions in the conserved Eya domain region of EYA1 have been identified in BOR patients; however, the molecular and developmental basis of organ defects that occurred in BOR syndrome is unclear. To understand how these point mutations cause disease, we have analyzed the functional importance of these Eya domain missense mutations with respect to protein complex formation and cellular localization. We have demonstrated that these point mutations do not alter protein localization. However, four mutations are crucial for protein-protein interactions in both yeast and mammalian cells. Our results provide insights into the molecular mechanisms of organ defects detected in human syndromes.
authors.affiliation: McLaughlin Research Institute for Biomedical Sciences, 1520 23rd Street South, Great Falls, MT 59405, USA.
authors.forename: C
authors.initials: C
authors.lastname: Buller
authors.forename: X
authors.initials: X
authors.lastname: Xu
authors.forename: V
authors.initials: V
authors.lastname: Marquis
authors.forename: R
authors.initials: R
authors.lastname: Schwanke
authors.forename: P X
authors.initials: PX
authors.lastname: Xu
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D019280:Branchio-Oto-Renal Syndrome / Q000235:genetics* / Q000473:pathology; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003001:Cloning, Molecular; D017124:Conserved Sequence; D004330:Drosophila; D029721:Drosophila Proteins; D004926:Escherichia coli; D005136:Eye Proteins; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D046911:Macromolecular Substances; D051379:Mice; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009687:Nuclear Proteins; D011233:Precipitin Tests; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D017027:Protein Tyrosine Phosphatases; D011506:Proteins; D017386:Sequence Homology, Amino Acid; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015533:Transcriptional Activation; D020798:Two-Hybrid System Techniques
chemical_list: D029721:Drosophila Proteins; D005136:Eye Proteins; D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; D046911:Macromolecular Substances; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011506:Proteins; C099236:SIX1 protein, human; C484762:SIX2 protein, human; C490947:Six1 protein, mouse; C087345:So protein, Drosophila; D015534:Trans-Activators; C103968:dac protein, Drosophila; C092694:eya protein, Drosophila; C104381:EYA1 protein, human; C501156:Eya1 protein, mouse; D017027:Protein Tyrosine Phosphatases