title: Mutation screening of the EYA1, SIX1, and SIX5 genes in a large cohort of patients harboring branchio-oto-renal syndrome calls into question the pathogenic role of SIX5 mutations.
abstract: Branchio-oto-renal (BOR) syndrome is an autosomal dominant disorder characterized by branchial, ear, and renal anomalies. Over 80 mutations in EYA1 have been reported in BOR. Mutations in SIX1, a DNA binding protein that associates with EYA1, have been reported less frequently. One group has recently described four missense mutations in SIX5 in five unrelated patients with BOR. Here, we report a screening of these three genes in a cohort of 140 patients from 124 families with BOR. We identified 36 EYA1 mutations in 42 unrelated patients, 2 mutations, and 1 change of unknown significance in SIX1 in 3 unrelated patients, but no mutation in SIX5. We did not find correlation between genotype and phenotype, and observed a high phenotypic variability between and within BOR families. We show the difficulty in establishing a molecular diagnosis strategy in BOR syndrome: the screening focusing on patients with typical BOR would detect a mutation rate of 76%, but would also miss mutations in 9% of patients with atypical BOR. We detected a deletion removing three EYA1 exons in a patient who was previously reported to carry the SIX5 Thr552Met mutation. This led us to reconsider the role of SIX5 in the development of BOR.
authors.affiliation: AP-HP, Service de Néphrologie Pédiatrique, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Krug
authors.forename: Vincent
authors.initials: V
authors.lastname: Morinière
authors.forename: Sandrine
authors.initials: S
authors.lastname: Marlin
authors.forename: Valérie
authors.initials: V
authors.lastname: Koubi
authors.forename: Heinz D
authors.initials: HD
authors.lastname: Gabriel
authors.forename: Estelle
authors.initials: E
authors.lastname: Colin
authors.forename: Dominique
authors.initials: D
authors.lastname: Bonneau
authors.forename: Rémi
authors.initials: R
authors.lastname: Salomon
authors.forename: Corinne
authors.initials: C
authors.lastname: Antignac
authors.forename: Laurence
authors.initials: L
authors.lastname: Heidet
mesh_terms: D019280:Branchio-Oto-Renal Syndrome / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics*; D017027:Protein Tyrosine Phosphatases / Q000235:genetics*
chemical_list: D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; C099236:SIX1 protein, human; C106687:SIX5 protein, human; C104381:EYA1 protein, human; D017027:Protein Tyrosine Phosphatases