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

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 recentl...

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Published in:	Human mutation Vol. 32; no. 2; pp. 183 - 190
Main Authors:	Krug, Pauline, Morinière, Vincent, Marlin, Sandrine, Koubi, Valérie, Gabriel, Heinz D, Colin, Estelle, Bonneau, Dominique, Salomon, Rémi, Antignac, Corinne, Heidet, Laurence
Format:	Journal Article
Language:	English
Published:	Hoboken Wiley Subscription Services, Inc., A Wiley Company 01-02-2011 Hindawi Limited Wiley
Subjects:	BOR syndrome Branchio-Oto-Renal Syndrome - genetics Branchio-Oto-Renal Syndrome - pathology Branchio-Oto-Renal Syndrome - physiopathology Cohort Studies developmental defect DNA Mutational Analysis EYA1 Female Homeodomain Proteins - genetics Humans Intracellular Signaling Peptides and Proteins - genetics Male Nuclear Proteins - genetics Protein Tyrosine Phosphatases - genetics SIX1 SIX5 Life Sciences
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Summary:	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. Hum Mutat 32:183-190, 2011.
Bibliography:	http://dx.doi.org/10.1002/humu.21402 ark:/67375/WNG-FM4TMBC7-C istex:5FF624C56350B7BC5AB9C8F6E714CE8C89471D59 Communicated by Ravi Savarirayan ArticleID:HUMU21402 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 ObjectType-Feature-1
ISSN:	1059-7794 1098-1004 1098-1004
DOI:	10.1002/humu.21402