Disease relevance of Branchio-Oto-Renal Syndrome

• Eya1 heterozygotes show renal abnormalities and a conductive hearing loss similar to BOR syndrome, whereas Eya1 homozygotes lack ears and kidneys due to defective inductive tissue interactions and apoptotic regression of the organ primordia [1].
• The human homolog of this gene, EYA1, has been shown to underly branchio-oto-renal (BOR) syndrome, an autosomal dominant disorder characterized by hearing loss with associated branchial and renal anomalies [2].
• Oto-facio-cervical (OFC) syndrome is a contiguous gene deletion syndrome involving EYA1: molecular analysis confirms allelism with BOR syndrome and further narrows the Duane syndrome critical region to 1 cM [3].
• Branchio-Oto-Renal (BOR) syndrome is an autosomal dominant, early developmental defect characterised by varying combinations of branchial (fistulas, sinuses, and cysts), outer, middle and inner ear, and renal anomalies [4].
• This is the first study of a BOR patient with congenital cholesteatoma and the second family in which cholesteatoma and anomalies of the facial nerve are described in patients with the BO/BOR syndrome [5].

High impact information on Branchio-Oto-Renal Syndrome

• SIX1 mutations cause branchio-oto-renal syndrome by disruption of EYA1-SIX1-DNA complexes [6].
• Recently, several point mutations that result in single amino acid substitutions in the conserved Eya domain region of EYA1 have been identified in BOR patients; however, the molecular and developmental basis of organ defects that occurred in BOR syndrome is unclear [7].
• Inner ear and kidney anomalies caused by IAP insertion in an intron of the Eya1 gene in a mouse model of BOR syndrome [2].
• In contrast, we report a new localization for the gene responsible for BOR syndrome which is more telomeric to an initial placement [8].
• Using Drosophila to decipher how mutations associated with human branchio-oto-renal syndrome and optical defects compromise the protein tyrosine phosphatase and transcriptional functions of eyes absent [9].

Biological context of Branchio-Oto-Renal Syndrome

• The human B22 subunit of the NADH-ubiquinone oxidoreductase maps to the region of chromosome 8 involved in branchio-oto-renal syndrome [10].
• This dosage assay, combined with microsatellite marker analysis, has identified de novo deletions of the EYA1 gene and surrounding region in two patients with complex phenotypes involving features of BOR syndrome [3].
• Advances in molecular genetics have recently revealed that mutations in the EYA1 gene are responsible for branchio-oto-renal (BOR) syndrome in European and other populations [11].

Anatomical context of Branchio-Oto-Renal Syndrome

• The presence of a widened vestibular aqueduct and progressive sensorineural hearing loss in the branchio-oto-renal syndrome. A family study [12].
• Hemifacial microsomia (HFM) and the branchio-oto-renal syndrome (BOR) are both associated with malformations of the external ears; preauricular tags, pits, or sinuses; and conductive or mixed hearing loss [13].

Gene context of Branchio-Oto-Renal Syndrome

• Clustering of mutations responsible for branchio-oto-renal (BOR) syndrome in the eyes absent homologous region (eyaHR) of EYA1 [14].
• Mutations in human EYA1 cause congenital Branchio-Oto-Renal (BOR) syndrome, while targeted inactivation of murine Eya1 impairs early developmental processes in multiple organs, including ear, kidney and skeletal system [15].
• Interestingly, these Six1 defects are very similar to phenotypes caused by mutations of Eya 1, which are responsible for the BOR syndrome in humans [16].
• Since several hereditary deafness disorders have been associated with mitochondrial mutations, NDUFB9 was considered a candidate gene for BOR syndrome [17].
• Impaired interactions between mouse Eyal harboring mutations found in patients with branchio-oto-renal syndrome and Six, Dach, and G proteins [18].

Analytical, diagnostic and therapeutic context of Branchio-Oto-Renal Syndrome

• Sequence analysis of the entire EYA1 coding region was performed for 20 unrelated patients affected by BOR syndrome, and six novel mutations were identified [14].
• To identify whether mutations in NDUFB9 are involved in causing the BOR syndrome, we screened 9 BOR families which did not show mutations in the EYA1 gene by heteroduplex analysis; however, no mutations were found [17].

References