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. / Ruf, Rainer G; Xu, Pin-Xian; Silvius, Derek; Otto, Edgar A; Beekmann, Frank; Muerb, Ulla T; Kumar, Shrawan; Neuhaus, Thomas J; Kemper, Markus J.; Raymond, Richard M; Brophy, Patrick D; Berkman, Jennifer; Gattas, Michael; Hyland, Valentine; Ruf, Eva-Maria; Schwartz, Charles; Chang, Eugene H; Smith, Richard J H; Stratakis, Constantine A; Weil, Dominique; Petit, Christine; Hildebrandt, Friedhelm.
In: P NATL ACAD SCI USA, Vol. 101, No. 21, 21, 2004, p. 8090-8095.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - SIX1 mutations cause branchio-oto-renal syndrome by disruption of EYA1-SIX1-DNA complexes.
AU - Ruf, Rainer G
AU - Xu, Pin-Xian
AU - Silvius, Derek
AU - Otto, Edgar A
AU - Beekmann, Frank
AU - Muerb, Ulla T
AU - Kumar, Shrawan
AU - Neuhaus, Thomas J
AU - Kemper, Markus J.
AU - Raymond, Richard M
AU - Brophy, Patrick D
AU - Berkman, Jennifer
AU - Gattas, Michael
AU - Hyland, Valentine
AU - Ruf, Eva-Maria
AU - Schwartz, Charles
AU - Chang, Eugene H
AU - Smith, Richard J H
AU - Stratakis, Constantine A
AU - Weil, Dominique
AU - Petit, Christine
AU - Hildebrandt, Friedhelm
PY - 2004
Y1 - 2004
N2 - 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.
AB - 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.
KW - Humans
KW - Amino Acid Sequence
KW - Molecular Sequence Data
KW - Base Sequence
KW - Gene Expression Regulation, Developmental
KW - Protein Structure, Tertiary
KW - Nuclear Proteins
KW - Cell Line
KW - Protein Binding
KW - Macromolecular Substances
KW - Genes, Reporter/genetics
KW - Mutation/genetics
KW - Trans-Activators/metabolism
KW - Branchio-Oto-Renal Syndrome/genetics
KW - DNA/genetics/metabolism
KW - Homeodomain Proteins/chemistry/genetics/metabolism
KW - Intracellular Signaling Peptides and Proteins
KW - Protein Tyrosine Phosphatases
KW - Humans
KW - Amino Acid Sequence
KW - Molecular Sequence Data
KW - Base Sequence
KW - Gene Expression Regulation, Developmental
KW - Protein Structure, Tertiary
KW - Nuclear Proteins
KW - Cell Line
KW - Protein Binding
KW - Macromolecular Substances
KW - Genes, Reporter/genetics
KW - Mutation/genetics
KW - Trans-Activators/metabolism
KW - Branchio-Oto-Renal Syndrome/genetics
KW - DNA/genetics/metabolism
KW - Homeodomain Proteins/chemistry/genetics/metabolism
KW - Intracellular Signaling Peptides and Proteins
KW - Protein Tyrosine Phosphatases
M3 - SCORING: Journal article
VL - 101
SP - 8090
EP - 8095
JO - P NATL ACAD SCI USA
JF - P NATL ACAD SCI USA
SN - 0027-8424
IS - 21
M1 - 21
ER -