Branchio-oto-renal syndrome (BOR): Novel mutations in the EYA1 gene, and a review of the mutational genetics of BOR

Department of Genetics, Boys Town National Research Hospital, Omaha, Nebraska 68164, USA.
Human Mutation (Impact Factor: 5.14). 04/2008; 29(4):537-44. DOI: 10.1002/humu.20691
Source: PubMed


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 (, 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.

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Available from: Uppala Radhakrishna, Oct 02, 2015
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    • "The minor allele of this SNP was present in only four individuals from four different families. Mutations in EYA were found in patients with brachio-oto-renal syndrome, as well as in individuals with isolated renal malformations [7,8]. Renal malformations can cause high blood pressure early in life. "
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    ABSTRACT: ABSTRACT : Growth mixture modelling, a less explored method in genetic research, addresses unobserved heterogeneity in population samples. We applied this technique to longitudinal data of the Framingham Heart Study. We examined systolic blood pressure (BP) measures in 1060 males from 692 families and detected three subclasses, which varied significantly in their developmental trajectories over time. The first class consisted of 60 high-risk individuals with elevated BP early in life and a steep increase over time. The second group of 131 individuals displayed first normal BP, but showed a significant increase over time and reached high BP values late in their life time. The largest group of 869 individuals could be considered a normative group with normal BP on all exams. To identify genetic modulators for this phenotype, we tested 2,340 single-nucleotide polymorphisms on chromosome 8 for association with the class membership probabilities of our model. The probability of being in Class 1 was significantly associated with a very rare variant (rs1445404) present in only four individuals from four different families located in the coding region of the gene EYA (eyes absent homolog 1 in Drosophila) (p = 1.39 x 10-13). Mutations in EYA are known to cause brachio-oto-renal syndrome, as well as isolated renal malformations. Renal malformations could cause high BP early in life. This result awaits replication; however, it suggests that analyzing genetic data stratified for high-risk subgroups defined by a unique development over time could be useful for the detection of rare mutations in common multi-factorial diseases.
    BMC proceedings 12/2009; 3 Suppl 7(Suppl 7):S114. DOI:10.1186/1753-6561-3-s7-s114
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    • "Haploinsufficiency is one of the mechanisms by which genetic mutations result in autosomal dominant disorders. The BOR/EYA1 pathway has been proposed to fall into this class (Zhang et al., 2004; Orten et al., 2008). Although it is clear "
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    ABSTRACT: The BOR (branchio-oto-renal) syndrome is a dominant disorder most commonly caused by mutations in the EYA1 (Eyes Absent 1) gene. Symptoms commonly include deafness and renal anomalies. We have used the embryos of the frog Xenopus laevis as an animal model for early ear development to examine the effects of different EYA1 mutations. Four eya1 mRNAs encoding proteins correlated with congenital anomalies in human were injected into early stage embryos. We show that the expression of mutations associated with BOR, even in the presence of normal levels of endogenous eya1 mRNA, leads to morphologically abnormal ear development as measured by overall otic vesicle size, establishment of sensory tissue and otic innervation. The molecular consequences of mutant eya1 expression were assessed by QPCR (quantitative PCR) analysis and in situ hybridization. Embryos expressing mutant eya1 showed altered levels of multiple genes (six1, dach, neuroD, ngnr-1 and nt3) important for normal ear development. These studies lend support to the hypothesis that dominant-negative effects of EYA1 mutations may have a role in the pathogenesis of BOR.
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    • "Genes associated with the olfactory epithelium include contactin 4 (CNTN4), Kallmann syndrome 1 sequence (KAL1), and olfactomedin 2 (OLFM2); genes associated with the ear include espin (ESPN), sine oculis homeobox homolog 1 (SIX1), and deafness, autosomal recessive 59 (DFNB59); and genes associated with the eye include eyes absent homolog 1 (EYA1), sidekick homolog 2 (SDK2), and dachshund homolog 1 (DACH1). Several of these, including KAL1, DFNB59 and EYA1 are associated with human genetic disorders that lead to sensory defects [26]-[28]. "
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