Mutational Analysis of EYA1, SIX1 and SIX5 Genes and Strategies for Management of Hearing Loss in Patients with BOR/BO Syndrome

Song, Mee Hyun; Kwon, Tae-Jun; Kim, Hui Ram; Jeon, Ju Hyun; Baek, Jeong‐In; Lee, Won-Sang; Kim, Un-Kyung; Choi, Jae Young

doi:10.1371/journal.pone.0067236

Cited by 39 publications

(51 citation statements)

References 30 publications

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“…In addition, it has been observed that mutations in the human genes EYA1, SIX1 and SIX5, cause the autosomal dominant syndrome Branchio-Oto-Renal, an early developmental defect characterized by varying combinations of branchial (fistulas, sinuses, and cysts), outer, middle and inner ear, as well as renal anomalies. (Song et al, 2013). The RT-PCR analysis confirms the presence of mRNA of Six1 and Eya1, both possible targets of mmu-miR-200c and mmu-miR-205.…”

Section: Resultsmentioning

confidence: 66%

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External ear microRNA expression profiles during mouse development

Torres¹,

Juárez²,

García³

et al. 2015

Int. J. Dev. Biol.

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MicroRNAs (miRNAs) comprise a class of approximately 22 nucleotide regulatory noncoding RNAs that play several roles in diverse biological processes. Recent reports suggest that embryonic development in mammals is accompanied by dynamic changes in miRNA expression; however, there is no information regarding the role of miRNAs in the development of the external ear. The aim of this study was to determine the stage-specific expression of miRNAs during mouse external ear development in order to identify potentially implicated miRNAs along with their possible targets. miRNA expression profiles from fetal mice pinnae and back skin tissues at 13.5 dpc and 14.5 dpc were obtained using an Affymetrix GeneChip miRNA 3.0 array. Biological triplicates for both tissues, each collected from a litter averaging 16 fetuses, were analyzed. The results were analyzed with Affymetrix's Transcriptome Analysis Console software to identify differentially expressed miRNAs. We observed differential expression of 40 miRNAs including some predicted to target genes implicated in external ear development, such as mmu-miR-10a, a miRNA known to modulate Hoxa1 mRNA levels, and mmu-miR-200c and mmu-miR-205. To our knowledge, this is the first miRNA expression profiling study of external ear development in mammals. These data could set the basis to understand the implications of miRNAs in normal external ear development KEY WORDS: miRNA, pinnae, auricle, microtia, GEO (GSE64945) In mammals, the outer ear is formed by the ear pinna (i.e., the auricle and the external ear), the external acoustic meatus (i.e., the ear canal), and the outer layer of the tympanic membrane (i.e., the eardrum). The outer ear develops as a result of complex tissue interactions between ectoderm and mesoderm during embryogenesis. Outer ear development is driven by the mesenchyme of the first and second pharyngeal arches and is controlled, at least in part, by the genes that determine the first and the second pharyngeal arch identity. The auricle is formed from six protuberances in the first and the second arches known as the auricular hillocks (Jones and Chuan, 1934;Mallo and Gridley, 1996). In mice, several genes involved in external ear development have been identified, including Hoxa2, Hoxa1, Hoxb1, Prrx1, Dlx1, Dlx5, Six1, Six4, Sall1, Tbx1, Bmp5, Fgf3, Fgf8, Fgf10 and Eya1. The genetic and cellular mechanisms underlying normal morphogenesis of the external Int.

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Section: Resultsmentioning

confidence: 66%

“…It has been reported that in mouse embryo, miR-10a expression follows a HoxB-like expression pattern with a common regulatory element (Tanzer et al, 2005). According to previous luciferase activity studies, it was suggested that miR-10a could be an inhibitor of the HOXA1 expression in megakaryocytic differentiation (Garzon et al, 2006).…”

Section: Resultsmentioning

confidence: 99%

External ear microRNA expression profiles during mouse development

Torres¹,

Juárez²,

García³

et al. 2015

Int. J. Dev. Biol.

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“…In particular, mutations in SIX1 , SIX5 , or EYA1 can lead to branchio-oto-renal (BOR) syndrome, a developmental disorder defined by hearing loss, bronchial fistulae, and renal anomalies 43 . EYA1 is the most commonly mutated gene in BOR syndrome with currently 14 known mutations located within the ED 11, 44, 45 , which contains both the SIX1 interaction site, as well as its tyrosine phosphatase activity 46 .…”

Section: The Role Of Six1 and Eya In Genetic Syndromesmentioning

confidence: 99%

The SIX1-EYA transcriptional complex as a therapeutic target in cancer

Blevins

Towers

Patrick

et al. 2015

Expert Opinion on Therapeutic Targets

107

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Introduction The SIX homeodomain proteins and the EYA family of co-activators form a bipartite transcription factor complex that promotes the proliferation and survival of progenitor cells during organogenesis and is down-regulated in most adult tissues. Abnormal over-expression of SIX1 and EYA in adult tissue is associated with the initiation and progression of diverse tumor types. Importantly, SIX1 and EYA are often co-overexpressed in tumors, and the SIX1-EYA2 interaction has been shown to be critical for metastasis in a breast cancer model. The EYA proteins also contain protein tyrosine phosphatase activity, which plays an important role in breast cancer growth and metastasis as well as directing cells to the repair pathway upon DNA damage. Areas covered This review provides a summary of the SIX1/EYA complex as it relates to development and disease and the current efforts to therapeutically target this complex. Expert opinion Recently, there have been an increasing number of studies suggesting that targeting the SIX1/EYA transcriptional complex will potently inhibit tumor progression. Although current attempts to develop inhibitors targeting this complex are still in the early stages, continued efforts towards developing better compounds may ultimately result in effective anti-cancer therapies.

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“…A novel deletion mutation, c.1381delA, was detected in the EYA1 gene, and the patient was heterozygous for this change (Figure 2A). This deletion causes a frameshift of amino acids and results in a truncated protein 43 in South Korea and Japan (Table 1) (10,(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29). In contrast, few mutations have been reported before in patients with BOR syndrome in Taiwan, China (Table 1) (7).…”

Section: Resultsmentioning

confidence: 99%