title: SIX1 mutation screening in 247 branchio-oto-renal syndrome families: a recurrent missense mutation associated with BOR.
abstract: Branchio-oto-renal syndrome (BOR) is a clinically heterogeneous autosomal dominant form of syndromic hearing loss characterized by variable hearing impairment, malformations of the pinnae, the presence of branchial arch remnants, and various renal abnormalities. Both EYA1 and SIX1 are expressed in developing otic, branchial and renal tissue. Consistent with this expression pattern, mutations in both genes cause BOR syndrome. Mutations in EYA1 are found in approximately 40% of patients with the BOR phenotype, however, the role of SIX1 is much lower. To date only three different SIX1 mutations have been described in BOR patients. The current screen of 247 BOR families detected five novel SIX1 mutations (c.50T>A, c.218A>C, c.317T>G, c.329G>A, c.334C>T) and one previously reported mutation (c.328C>T) seen in 5 unrelated families. All mutations are within the protein-binding Six domain. Phenotypic variability was high in these BOR families. Seven of the eight known SIX1 mutations are missense and the one in frame deletion is predicted to be functionally similar. The wide phenotypic variability precludes making genotype-phenotype correlations at this time.
authors.affiliation: Doris Duke Clinical Research Fellowship, Head and Neck Surgery, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Kochhar
authors.forename: Dana J
authors.initials: DJ
authors.lastname: Orten
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Sorensen
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Fischer
authors.forename: Cor W R J
authors.initials: CW
authors.lastname: Cremers
authors.forename: William J
authors.initials: WJ
authors.lastname: Kimberling
authors.forename: Richard J H
authors.initials: RJ
authors.lastname: Smith
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D019280:Branchio-Oto-Renal Syndrome / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D005799:Genes, Dominant; D005820:Genetic Testing; D018398:Homeodomain Proteins / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D007438:Introns; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D017434:Protein Structure, Tertiary; D017027:Protein Tyrosine Phosphatases / Q000235:genetics; D017386:Sequence Homology, Amino Acid
chemical_list: D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; C099236:SIX1 protein, human; C104381:EYA1 protein, human; D017027:Protein Tyrosine Phosphatases