Transcription Factor SIX5 Is Mutated in Patients with Branchio-Oto-Renal Syndrome

Department of Pediatrics and of Human Genetics, University of Michigan, Ann Arbor, MI, USA.
The American Journal of Human Genetics (Impact Factor: 10.93). 05/2007; 80(4):800-4. DOI: 10.1086/513322
Source: PubMed


Branchio-oto-renal syndrome (BOR) is an autosomal dominant developmental disorder characterized by the association of branchial arch defects, hearing loss, and renal anomalies. Mutations in EYA1 are known to cause BOR. More recently, mutations in SIX1, which interacts with EYA1, were identified as an additional cause of BOR. A second member of the SIX family of proteins, unc-39 (SIX5), has also been reported to directly interact with eya-1 in Caenorhabditis elegans. We hypothesized that this interaction would be conserved in humans and that interactors of EYA1 represent good candidate genes for BOR. We therefore screened a cohort of 95 patients with BOR for mutations in SIX5. Four different heterozygous missense mutations were identified in five individuals. Functional analyses of these mutations demonstrated that two mutations affect EYA1-SIX5 binding and the ability of SIX5 or the EYA1-SIX5 complex to activate gene transcription. We thereby identified heterozygous mutations in SIX5 as a novel cause of BOR.

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Available from: Dana Orten, Jun 04, 2014
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    • "Six1, Six2, and Six5 are all expressed in the developing kidney (Ohto et al., 1998). Mutations in SIX1 (Ruf et al., 2004) and SIX5 (Hoskins et al., 2007) genes in humans have been associated to the branchio-oto-renal (BOR) syndrome, which is characterized by renal hypodysplasia, cervical fistulae, and ear anomalies (Vervoort et al., 2002; Weber et al., 2008a). This syndrome is most frequently associated to mutations in the EYA1 gene, an ortholog of Drosophila eye. "
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    ABSTRACT: Congenital anomalies of the kidney and urinary tract (CAKUT) represent a broad range of disorders that result from abnormalities of the urinary collecting system, abnormal embryonic migration of the kidneys, or abnormal renal parenchyma development. These disorders are commonly found in humans, accounting for 20-30% of all genetic malformations diagnosed during the prenatal period. It has been estimated that CAKUT are responsible for 30-50% of all children with chronic renal disease worldwide and that some anomalies can predispose to adult-onset diseases, such as hypertension. Currently, there is much speculation regarding the pathogenesis of CAKUT. Common genetic background with variable penetrance plays a role in the development of the wide spectrum of CAKUT phenotypes. This review aims to summarize the possible mechanisms by which genes responsible for kidney and urinary tract morphogenesis might be implicated in the pathogenesis of CAKUT. Birth Defects Research (Part C), 2014. © 2014 Wiley Periodicals, Inc. Copyright © 2014 Wiley Periodicals, Inc.
    Full-text · Article · Nov 2014 · Birth Defects Research Part C Embryo Today Reviews
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    • "Expression studies in mice have shown that Eya1 is co-expressed with Six1 and Six2 in branchial arches, ear and kidney during development [15], [16]. Indeed, mutations in Six gene family members such as SIX1 and SIX5 also cause BOR syndrome while mutations in SIX2 have been reported in patients with renal hypodysplasia, a phenotype observed in patients with BOR syndrome [17]–[19]. "
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    ABSTRACT: Mutations in the human EYA1 gene have been associated with several human diseases including branchio-oto (BO) and branchio-oto-renal (BOR) syndrome, as well as congenital cataracts and ocular anterior segment anomalies. BOR patients suffer from severe malformations of the ears, branchial arches and kidneys. The phenotype of Eya1-heterozygous mice resembles the symptoms of human patients suffering from BOR syndrome. The Eya1 gene encodes a multifunctional protein that acts as a protein tyrosine phosphatase and a transcriptional coactivator. It has been shown that Eya1 interacts with Six transcription factors, which are also required for nuclear translocation of the Eya1 protein. We investigated the effects of seven disease-causing Eya1 missense mutations on Eya1 protein function, in particular cellular localization, ability to interact with Six proteins, and protein stability. We show here that the BOR-associated Eya1 missense mutations S454P, L472R, and L550P lead to enhanced proteasomal degradation of the Eya1 protein in mammalian cells. Moreover, Six proteins lead to a significant stabilization of Eya1, which is caused by Six-mediated protection from proteasomal degradation. In case of the mutant L550P, loss of interaction with Six proteins leads to rapid protein degradation. Our observations suggest that protein destabilization constitutes a novel disease causing mechanism for Eya1.
    Full-text · Article · Jan 2014 · PLoS ONE
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    • "Mutations in SIX1 gene (MIM 601295), the human homolog of sine oculis, encoding a DNA binding protein that interacts with EYA1, have also been associated with BOR syndrome although less frequently than EYA1 mutations [14,15]. Recently, mutations in another SIX family member, SIX5 (MIM 610896), have been reported in patients with BOR syndrome [16]. SIX5 homologous interacts with eya-1 in Caenorhabditis elegans. "
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    ABSTRACT: Background Branchio-oto-renal (BOR) syndrome is an autosomal dominant disorder characterized by branchial, ear, and renal anomalies. The most common gene mutated in BOR patients is EYA1, the human homolog of the Drosophila eyes absent gene, while mutations in SIX1 gene, the human homolog of sine oculis, encoding a DNA binding protein interacting with EYA1, have been reported less frequently. Recently, mutations in another SIX family member, SIX5, have been described in BOR patients, however, this association has not been confirmed by other groups. Case presentation In this study, we have clinically and genetically characterized a proband that displayed hearing loss, pre-auricular pits, branchial fistulae, hypoplasia of the left kidney, bilateral mild hydronephrosis, progressive proteinuria and focal glomerulosclerosis. Mutational analysis of EYA1 gene revealed a novel splice site mutation, c.1475 + 1G > C, that affects EYA1 splicing and produces an aberrant mRNA transcript, lacking exon 15, which is predicted to encode a truncated protein of 456 aa. Conclusion This report provided the functional description of a novel EYA1 splice site mutation and described for the first time a case of BOR syndrome associated with the atypical renal finding of focal glomerulosclerosis, highlighting the importance of molecular testing and detailed clinical evaluation to provide accurate diagnosis and appropriate genetic counselling.
    Full-text · Article · Mar 2013 · BMC Nephrology
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