title: Branchio-oto-renal syndrome: detection of EYA1 and SIX1 mutations in five out of six Danish families by combining linkage, MLPA and sequencing analyses.
abstract: The branchio-oto-renal (BOR) syndrome is an autosomal-dominant disorder characterized by hearing loss, branchial and renal anomalies. BOR is genetically heterogeneous and caused by mutations in EYA1 (8q13.3), SIX1 (14q23.1), SIX5 (19q13.3) and in an unidentified gene on 1q31. We examined six Danish families with BOR syndrome by assessing linkage to BOR loci, by performing EYA1 multiplex ligation-dependent probe amplification (MLPA) analysis for deletions and duplications and by sequencing of EYA1, SIX1 and SIX5. We identified four EYA1 mutations (c.920delG, IVS10-1G>A, IVS12+4A>G and p.Y591X) and one SIX1 mutation (p.W122R), providing a molecular diagnosis in five out of the six families (83%). The present, yet preliminary, observation that renal and temporal bone malformations are less frequent in SIX1-related disease suggests a slightly different clinical profile compared to EYA1-related disease. Unidentified mutations impairing mRNA expression or further genetic heterogeneity may explain the lack of mutation finding in one family despite LOD score indications of EYA1 involvement.
authors.affiliation: Wilhelm Johannsen Centre for Functional Genome Research, Section of Genetics, Institute of Cellular and Molecular Medicine, The Panum Institute, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Kirsten Marie
authors.initials: KM
authors.lastname: Sanggaard
authors.forename: Nanna Dahl
authors.initials: ND
authors.lastname: Rendtorff
authors.forename: Klaus Wilbrandt
authors.initials: KW
authors.lastname: Kjaer
authors.forename: Hans
authors.initials: H
authors.lastname: Eiberg
authors.forename: Torsten
authors.initials: T
authors.lastname: Johnsen
authors.forename: Steen
authors.initials: S
authors.lastname: Gimsing
authors.forename: Jørgen
authors.initials: J
authors.lastname: Dyrmose
authors.forename: Kristian Otto
authors.initials: KO
authors.lastname: Nielsen
authors.forename: Kasper
authors.initials: K
authors.lastname: Lage
authors.forename: Lisbeth
authors.initials: L
authors.lastname: Tranebjaerg
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019280:Branchio-Oto-Renal Syndrome / Q000235:genetics* / Q000473:pathology; D005260:Female; D008040:Genetic Linkage; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D007668:Kidney / Q000002:abnormalities; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics*; D021141:Nucleic Acid Amplification Techniques; D010375:Pedigree; D017354:Point Mutation; D017027:Protein Tyrosine Phosphatases / Q000235:genetics*; D017422:Sequence Analysis, DNA; D013701:Temporal Bone / Q000002:abnormalities
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