Branchio-oto-renal syndrome (BOR): novel mutations in theEYA1gene, and a review of the mutational genetics of BOR

Abstract

Branchio-oto-renal syndrome (BOR) is an autosomal dominant disorder characterized by the association of branchial and external ear malformations, hearing loss, and renal anomalies. The phenotype varies from ear pits to profound hearing loss, branchial fistulae, and kidney agenesis. The most common gene mutated in BOR families is EYA1, a transcriptional activator. Over 80 different disease-causing mutations have been published (www.healthcare.uiowa.edu/labs/pendredandbor/, last accessed 20 November 2007). We analyzed the EYA1 coding region (16 exons) from 435 families (345 at the University of Iowa [UI] and 95 at Boys Town National Research Hospital [BTNRH], including five at both) and found 70 different EYA1 mutations in 89 families. Most of the mutations (56/70) were private. EYA1 mutations were found in 31% of families (76/248) fitting established clinical criteria for BOR and 7% of families with questionable BOR phenotype (13/187). Severity of the phenotype did not correlate with type of mutation nor with the domain involved. These results add considerably to the spectrum of EYA1 mutations associated with BOR and indicate that the BOR phenotype is an indication for molecular studies to diagnose EYA1-associated BOR.

A recurrent EYA1 mutation causing alternative RNA splicing in branchio‐oto‐renal syndrome: Implications for molecular diagnostics and disease mechanism

“…Our overall mutation detection rate is higher than the 31% reported from EYA1 testing using denaturing high performance liquid chromatography (DHPLC) prior to sequencing [Orten et al, 2008], but is comparable to a recent report that four of six BOR families had EYA1 mutations when tested by methods similar to those used in our study [Sanggaard et al, 2007]. The use of DHPLC [Migliosi et al, 2004] may have led to underestimation of the contribution of EYA1 mutations to BOR, as DHPLC has reduced sensitivity.…”

“…BOR syndrome has variable expressivity within and among families. EYA1 mutations have been found in 30-70% of patients with BOR, with the majority of mutations novel [Abdelhak et al, 1997a;Chang et al, 2004;Sanggaard et al, 2007;Orten et al, 2008].…”

The Canonical Wnt Signal Restricts the Glycogen Synthase Kinase 3/Fbw7-Dependent Ubiquitination and Degradation of Eya1 Phosphatase

“…To examine the potential pathophysiological significance of Eya1 ubiquitin modification, we analyzed a number of missense mutations within the conserved C-terminal domain identified in patients with BOR syndrome (9,25,26). Among them, the S487P and L505R point mutants have a significantly lower level of tyrosine phosphatase catalytic activity (23,27).…”

SIX1mutation screening in 247 branchio-oto-renal syndrome families: a recurrent missense mutation associated with BOR

“…Primers designed by Polymorphic are available upon request. EYA1 mutations were later found in 25 probands (Orten et al 2008), which are not included in our 247 EYA1 negative probands. Poor sequence had been obtained for the 3 prime segment of SIX1, exon 1, so in the remaining 40 probands this amplicon (bp.c.208 to 560+61) was sequenced on a Beckman-Coulter CEQ-8000 using the CEQ DTCS-Quick Start Kit with previously reported primers (Ruf et al, 2004, supplementary data).…”