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

Abstract

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.

Branchio–oto–renal syndrome: detection of EYA1 and SIX1 mutations in five out of six Danish families by combining linkage, MLPA and sequencing analyses

“…11 -13 After submission of this article, the SIX1 homologue SIX5 (19q13.3) has been found to be mutated in BOR patients. 14 At least 116 different EYA1 mutations and rearrangements have been reported (isoform B). 3,15,16 By contrast, only few mutations have been reported in the SIX genes.…”

“…Thus, so far, five unrelated families have been published with three different mutations in SIX1, 10,17 and five BOR individuals have been identified with four different SIX5 missense mutations. 14 Alternative splicing of EYA1 produces four transcript variants, expressing three different isoforms with the longest isoform having 18 exons. 3 Eya family members (Eya1 -4) are defined by a conserved B275 amino-acid C-terminal domain, referred to as the Eya domain and which possesses protein phosphatase activity.…”

SIX2 and BMP4 Mutations Associate With Anomalous Kidney Development

“…5 Six1, Six2, and Six5 are all expressed in the developing kidney, 6 and human mutations in SIX1 and SIX5 have been identified in patients with EYA1-negative Branchio-oto-renal (BOR) syndrome that is characterized by RHD, cervical fistulae, and ear anomalies. 7,8 The role of Six2 for kidney development is further supported by the phenotype of the Six2 knockout mouse that presents with severe dysplasia of the kidneys comparable to human RHD. 4 Microarray studies indicated that murine Six2 expression in the MM is highly upregulated at E12.5, 9 the stage of UB, together with Gdnf and members of the Hox families Hoxa 11 and Hoxd 11, which are crucial for normal kidney development.…”

HPPD: A newly recognized autosomal dominant disorder involving hypertelorism, preauricular sinus, punctal pits, and deafness mapping to chromosome 14q31

“…Given the overlap in the phenotype seen between our family and BOR/BO syndrome, it is possible that mutations within the EYA-SIX gene network [Rebay et al, 2005] could underlie the manifestations seen in our pedigree. In addition, paralogs of EYA and SIX are ideal candidates for mutation screening as genes with overlapping functions and expression patterns or gene products that interact with each other could lead to the development of similar disease phenotypes [Hoskins et al, 2007]. Conversely, these candidate gene approaches to mutation screening would fail to identify any new genes that have not been previously characterized.…”

“…Patients with BOR/BO syndrome may have conductive, sensorineural, or mixed type hearing loss which may be stable or progressive with severity ranging from mild to profound [Fraser et al, 1980]. To date, mutations in three genes, EYA1 [Abdelhak et al, 1997], SIX1 [Ruf et al, 2004;Ito et al, 2006], and SIX5 [Hoskins et al, 2007], have been found in patients with BOR/BO syndrome.…”