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

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 BOR͞BO 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 BOR͞BO 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 proteinprotein 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 BOR͞BO offers insights into the molecular basis of otic and renal developmental diseases in humans.

Xeya3 regulates survival and proliferation of neural progenitor cells within the anterior neural plate of Xenopus embryos

“…In vertebrates, it has been demonstrated that EYA1/2 and SIX1 interact physically and are expressed in sensorial placodes as well as in the developing kidney. Consistently, mutations in either Eya1 or Six1 underlie the branchio-oto-renal (BOR) syndrome, which is characterized by anomalies of face, ear, and kidneys (Abdelhak et al, 1997;Ruf et al, 2004;Kozlowski et al, 2005). Furthermore, EYA2 cooperates with SIX1 and DACH2 to regulate muscle development (Heanue et al, 1999), and reported activities of EYA3 in cell culture depend on the presence of SIX1 (Li et al, 2003).…”

How to make a teleost adenohypophysis: Molecular pathways of pituitary development in zebrafish

“…In humans, mutations in SIX1 have been found to be linked to the Branchio Oto Renal Syndrome (BOR, OMIM 113650), a genetic disorder that includes malformations of the ear and cysts in the neck, hearing loss, and malformations of the kidney. According to the autosomal dominant mode of BOR inheritance, the corresponding mutations in human SIX1 appears to confer dominant-negative properties to the transcription factor (Kochhar et al, 2008, Ruf et al, 2004. One of the antimorphic human mutations disrupts the conserved valine at position 17, right next to the cysteine mutated in the zebrafish fr16 allele (Fig.…”

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

“…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.…”