ß 2007 Wiley-Liss, Inc. American Journal of Medical Genetics Part A 143A:1671–1678 (2007) Research Review Branchio-Oto-Renal Syndrome Amit Kochhar, 1 Stephanie M. Fischer, 1 William J. Kimberling, 2 and Richard J.H. Smith 1 * 1 Molecular Otolaryngology Research Laboratories, University of Iowa, Iowa City, Iowa 2 Boys Town National Research Hospital, Omaha, Nebraska Received 31 July 2006; Accepted 1 October 2006 Branchio-oto-renal syndrome, a phenotype consisting of hearing loss, auricular malformations, branchial arch rem- nants, and renal anomalies is now recognized as one of the more common forms of autosomal dominant syndromic hearing impairment. Three loci known to be associated with the BOR phenotype have been identified and two genes that act in a regulatory network have been cloned, EYA1 and SIX1. EYA1 and SIX1 are homologous to genes involved in Drosophila eye development, eyes absent gene (eya), and sine oculis (so), respectively. EYA1, a transcriptional co- activator has a conserved, 271-amino acid, C-terminal known as the Eya Domain (ED). SIX1 has two highly conserved domains; a homeodomain (HD) and a specific Six-domain (SD) whose products function as transcription factors with specific DNA-binding activity that are crucial for protein– protein interaction. To determine the molecular basis for the organ defects that occur in BOR syndrome, many studies have focused on the effects of mutations to EYA and effects of mutations of the EYA-SIX regulatory system. However, over 60% of BOR syndrome patients do not have known mutations in EYA1 and relatively little is known about mutations to SIX1. Further evaluation of SIX1 and its related target genes may provide a better understanding of the pathophysiology of BOR syndrome and offer greater clues to the disease mechanisms. ß 2007 Wiley-Liss, Inc. Key words: branchio-otic syndrome 1; BOS1; BOS2; BOS3 branchio-oto-renal syndrome; BOR syndrome; EYA1; hear- ing loss; syndromic hearing loss; SIX1 How to cite this article: Kochhar A, Fischer SM, Kimberling WJ, Smith RJH. 2007. Branchio-oto-renal syndrome. Am J Med Genet Part A 143A:1671 – 1678. INTRODUCTION The development of the vertebrate ear and periotic tissues is directed by a series of tissue movements and inductive interactions that promote spatial programming and cell differentiations [Noden and Van De Water, 1992]. The identification of genes involved in these processes is improving our under- standing of the complexity of ear development and the molecular pathogenesis of certain forms of genetic hearing defects. Genetic hearing loss is divided into two categories, non-syndromic (hearing impairment occurring in isolation) and syndromic (hearing impairment in association with other physical anomalies). Over 400 forms of syndromic deafness have been described in which hearing loss is an intrinsic part. Many of these syndromes can be classified as early developmental defects, demon- strated by the abnormal formation of one or more compartments (outer, middle, and inner) of the ear [Gorlin et al., 1995; Kalatzis et al., 1998]. In 1864, Heusinger first recognized an association between hearing impairment, preauricular pits, and branchial fistulae. However, it was not until a century later that Melnick and Fraser first comprehensively described the specific phenotypes. Subsequently, branchio-oto-renal syndrome, BOR (OMIM 113650), was defined to include hearing loss, auricular malformations, branchial arch remnants, and renal anomalies [Melnick et al., 1975; Fraser et al., 1978]. Many other clinical features—such as abnormal- ities of the face, palate, ureters, and bladder, dysfunction of the lacrimal system, otitis media, and shoulder abnormalities—have also been asso- ciated with BOR syndrome [Fitch and Sorolovitz, 1976; Cremers and Fikkers-Van Noord, 1980; Preisch et al., 1985; Heimler and Lieber, 1986; Pennie and Marres, 1992]. Observation of these other features has brought varied nomenclature to the disease. Grant sponsor: NIH; Grant number: DC03544. *Correspondence to: Richard J.H. Smith, Department of Otolaryngol- ogy-Head & Neck Surgery, Molecular Otolaryngology Research Labora- tories, 5270 CBRB, The University of Iowa, Iowa City, IA 52242. E-mail: richard-smith@uiowa.edu DOI 10.1002/ajmg.a.31561