SIX1 mutations cause branchio-oto-renal syndrome by disruption of EYA1–SIX1–DNA complexes

Rainer G Ruf; Pin-Xian Xu; Derek Silvius; Edgar A Otto; Frank Beekmann; Ulla T Muerb; Shrawan Kumar; Thomas J Neuhaus; Markus J Kemper; Richard M Raymond; Patrick D Brophy; Jennifer Berkman; Michael Gattas; Valentine Hyland; Eva-Maria Ruf; Charles Schwartz; Eugene H Chang; Richard J. H Smith; Constantine A Stratakis; Dominique Weil; Christine Petit; Friedhelm Hildebrandt

doi:10.1073/pnas.0308475101

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SIX1 mutations cause branchio-oto-renal syndrome by disruption of EYA1–SIX1–DNA complexes

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SIX1 mutations cause branchio-oto-renal syndrome by disruption of EYA1–SIX1–DNA complexes

Rainer G Ruf, Pin-Xian Xu, Derek Silvius, Edgar A Otto, Frank Beekmann, Ulla T Muerb, Shrawan Kumar, Thomas J Neuhaus, Markus J Kemper, Richard M Raymond, …

Proceedings of the National Academy of Sciences - PNAS, Vol.101(21), pp.8090-8095

05/25/2004

DOI: 10.1073/pnas.0308475101

PMCID: PMC419562

PMID: 15141091

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Abstract

Urinary tract malformations constitute the most frequent cause of chronic renal failure in the first two decades of life. Branchio-otic (BO) syndrome is an autosomal dominant developmental disorder characterized by hearing loss. In branchio-oto-renal (BOR) syndrome, malformations of the kidney or urinary tract are associated. Haploinsufficiency for the human gene EYA1, a homologue of the Drosophila gene eyes absent (eya), causes BOR and BO syndromes. We recently mapped a locus for BOR/BO syndrome (BOS3) to human chromosome 14q23.1. Within the 33-megabase critical genetic interval, we located the SIX1, SIX4, and SIX6 genes, which act within a genetic network of EYA and PAX genes to regulate organogenesis. These genes, therefore, represented excellent candidate genes for BOS3. By direct sequencing of exons, we identified three different SIX1 mutations in four BOR/BO kindreds, thus identifying SIX1 as a gene causing BOR and BO syndromes. To elucidate how these mutations cause disease, we analyzed the functional role of these SIX1 mutations with respect to protein-protein and protein-DNA interactions. We demonstrate that all three mutations are crucial for Eya1-Six1 interaction, and the two mutations within the homeodomain region are essential for specific Six1-DNA binding. Identification of SIX1 mutations as causing BOR/BO offers insights into the molecular basis of otic and renal developmental diseases in humans.

Biological Sciences

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Title: Subtitle: SIX1 mutations cause branchio-oto-renal syndrome by disruption of EYA1–SIX1–DNA complexes
Creators: Rainer G Ruf - Departments of
Pin-Xian Xu - Departments of
Derek Silvius - Departments of
Edgar A Otto - Departments of
Frank Beekmann - Departments of
Ulla T Muerb - Departments of
Shrawan Kumar - Departments of
Thomas J Neuhaus - Departments of
Markus J Kemper - Departments of
Richard M Raymond - Departments of
Patrick D Brophy - Departments of
Jennifer Berkman - Departments of
Michael Gattas - Departments of
Valentine Hyland - Departments of
Eva-Maria Ruf - Departments of
Charles Schwartz - Departments of
Eugene H Chang - Departments of
Richard J. H Smith - Departments of
Constantine A Stratakis - Departments of
Dominique Weil - Departments of
Christine Petit - Departments of
Friedhelm Hildebrandt - Departments of
Resource Type: Journal article
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.101(21), pp.8090-8095
DOI: 10.1073/pnas.0308475101
PMID: 15141091
PMCID: PMC419562
NLM abbreviation: Proc Natl Acad Sci U S A
ISSN: 0027-8424
eISSN: 1091-6490
Publisher: National Academy of Sciences
Language: English
Date published: 05/25/2004
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Otolaryngology; Internal Medicine
Record Identifier: 9984006457002771

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