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BMC Medical Genetics Aug 2018Branchio-oto-renal (BOR) syndrome is a dominant autosomal disorder characterized by phenotypes such as hearing loss, branchial fistulae, preauricular pits, and renal...
BACKGROUND
Branchio-oto-renal (BOR) syndrome is a dominant autosomal disorder characterized by phenotypes such as hearing loss, branchial fistulae, preauricular pits, and renal abnormalities. EYA1, the human homolog of the Drosophila "eye absent" gene on chromosome 8q13.3, is recognized as one of the most important genes associated with BOR syndrome.
METHODS
The proposita in this study was a 5-year-old Chinese girl with hearing loss, bilateral otitis media with effusion, microtia, facial hypoplasia, palatoschisis, and bilateral branchial cleft fistulae. The girl's family members, except two who were deceased, agreed to undergo clinical examination. We collected blood samples from 10 family members, including six who were affected by the syndrome. Genomic DNA was extracted and subjected to Sanger sequencing. A minigene assay was performed to confirm whether splicing signals were altered. In addition, we performed western blotting to determine alterations in protein levels of the wild-type and mutant gene.
RESULTS
Clinical tests showed that some of the family members met the criteria for BOR syndrome. The affected members harbored a novel heterozygous nonsense variation in exon 11 of EYA1, whereas no unaffected member carried the mutation at this position. Functional experiments did not detect abnormal splicing at the RNA level; however, western blotting showed that the mutated protein was truncated.
CONCLUSIONS
This study reports a novel mutation associated with BOR syndrome in a Chinese family. We highlight the usefulness of genetic testing in the diagnosis of BOR syndrome. Thus, we believe that this report would benefit clinicians in this field.
Topics: Asian People; Branchio-Oto-Renal Syndrome; Child, Preschool; Codon, Nonsense; DNA; Exons; Female; Hearing Loss; Humans; Intracellular Signaling Peptides and Proteins; Male; Nuclear Proteins; Otitis Media; Pedigree; Phenotype; Protein Tyrosine Phosphatases
PubMed: 30086703
DOI: 10.1186/s12881-018-0653-2 -
AJNR. American Journal of Neuroradiology Dec 2018Branchio-oto-renal syndrome is an important syndromic cause of hearing loss. Our aim was to determine the test characteristics of the unwound cochlea on temporal bone CT...
BACKGROUND AND PURPOSE
Branchio-oto-renal syndrome is an important syndromic cause of hearing loss. Our aim was to determine the test characteristics of the unwound cochlea on temporal bone CT for the diagnosis of branchio-oto-renal syndrome in a cohort of children with hearing loss.
MATERIALS AND METHODS
Patients were identified retrospectively with a clinical diagnosis of branchio-oto-renal syndrome and CT imaging of the temporal bones. Age-matched controls were also identified with sensorineural hearing loss not related to a diagnosis of branchio-oto-renal syndrome and CT imaging of the temporal bones. All examinations were reviewed by 2 neuroradiologists blinded to the diagnosis of branchio-oto-renal syndrome versus controls for the absence/presence of an unwound cochlea defined as anteromedial rotation and displacement of the middle and apical turns away from the basal turn.
RESULTS
The final study group comprised 9 patients with branchio-oto-renal syndrome (age range, 1-14 years; mean age, 8.0 ± 4.3 years) and 50 control patients (age range, 1-16 years; mean age, 7.9 ± 4.1 years). The cochlea was subjectively abnormal in all 9 patients. In 8 patients (89%), imaging demonstrated a typical unwound cochlear morphology. By contrast, none of the control subjects demonstrated an unwound cochlea on either side. Statistically, the unwound cochlea was significantly more frequent in the branchio-oto-renal group compared with controls ( < .001). The unwound cochlea was 89% sensitive and 100% specific for the diagnosis of branchio-oto-renal syndrome.
CONCLUSIONS
The unwound cochlea is a specific imaging marker of branchio-oto-renal syndrome. These findings further support the diagnostic accuracy and therefore the utility of temporal bone imaging in the diagnosis of this disorder.
Topics: Adolescent; Branchio-Oto-Renal Syndrome; Child; Child, Preschool; Cochlea; Female; Humans; Infant; Male; Retrospective Studies; Temporal Bone; Tomography, X-Ray Computed
PubMed: 30385470
DOI: 10.3174/ajnr.A5856 -
Disease Models & Mechanisms Mar 2020Single-nucleotide mutations in human result in amino acid substitutions in either the protein-protein interaction domain or the homeodomain, and cause ∼4% of...
Single-nucleotide mutations in human result in amino acid substitutions in either the protein-protein interaction domain or the homeodomain, and cause ∼4% of branchio-otic (BOS) and branchio-oto-renal (BOR) cases. The phenotypic variation between patients with the same mutation, even within affected members of the same family, make it difficult to functionally distinguish between the different mutations. We made four of the BOS/BOR substitutions in the Six1 protein (V17E, R110W, W122R, Y129C), which is 100% identical to human in both the protein-protein interaction domain and the homeodomain, and expressed them in embryos to determine whether they cause differential changes in early craniofacial gene expression, otic gene expression or otic morphology. We confirmed that, similar to the human mutants, all four mutant Six1 proteins access the nucleus but are transcriptionally deficient. Analysis of craniofacial gene expression showed that each mutant causes specific, often different and highly variable disruptions in the size of the domains of neural border zone, neural crest and pre-placodal ectoderm genes. Each mutant also had differential effects on genes that pattern the otic vesicle. Assessment of the tadpole inner ear demonstrated that while the auditory and vestibular structures formed, the volume of the otic cartilaginous capsule, otoliths, lumen and a subset of the hair cell-containing sensory patches were reduced. This detailed description of the effects of BOS/BOR-associated mutations in the embryo indicates that each causes subtle changes in gene expression in the embryonic ectoderm and otocyst, leading to inner ear morphological anomalies.
Topics: Amino Acid Sequence; Animals; Branchio-Oto-Renal Syndrome; Ear; Gene Expression Regulation, Developmental; HEK293 Cells; Homeodomain Proteins; Humans; Mutation; Neural Crest; Otolithic Membrane; Protein Tyrosine Phosphatases; Skull; Transcription, Genetic; Xenopus Proteins; Xenopus laevis
PubMed: 31980437
DOI: 10.1242/dmm.043489 -
Journal of Developmental Biology Jun 2021Several single-nucleotide mutations in underlie branchio-otic/branchio-oto-renal (BOR) syndrome, but the clinical literature has not been able to correlate different...
Several single-nucleotide mutations in underlie branchio-otic/branchio-oto-renal (BOR) syndrome, but the clinical literature has not been able to correlate different variants with specific phenotypes. We previously assessed whether variants in either the cofactor binding domain (V17E, R110W) or the DNA binding domain (W122R, Y129C) might differentially affect early embryonic gene expression, and found that each variant had a different combination of effects on neural crest and placode gene expression. Since the otic vesicle gives rise to the inner ear, which is consistently affected in BOR, herein we focused on whether the variants differentially affected the otic expression of genes previously found to be likely Six1 targets. We found that V17E, which does not bind Eya cofactors, was as effective as wild-type Six1 in reducing most otic target genes, whereas R110W, W122R and Y129C, which bind Eya, were significantly less effective. Notably, V17E reduced the otic expression of , whereas R110W, W122R and Y129C expanded it. Since each mutant has defective transcriptional activity but differs in their ability to interact with Eya cofactors, we propose that altered cofactor interactions at the mutated sites differentially interfere with their ability to drive otic gene expression, and these differences may contribute to patient phenotype variability.
PubMed: 34208995
DOI: 10.3390/jdb9030025 -
Acta Radiologica Open Jul 2019Branchio-oto-renal syndrome is a rare genetic disorder that affects multiple organ systems. Temporal bone abnormalities include the unwound appearance of the cochlea...
Branchio-oto-renal syndrome is a rare genetic disorder that affects multiple organ systems. Temporal bone abnormalities include the unwound appearance of the cochlea which is common in this syndrome. This appearance can prompt renal imaging and evaluation. Presented here are two cases of branchio-oto-renal syndrome with dysplastic cochleae. A branchial cleft sinus and renal dysplasia were also present in one of the cases.
PubMed: 31384484
DOI: 10.1177/2058460119861606 -
Medicine Oct 2022Branchio-oto-renal (BOR) syndrome is an autosomal-dominant disorder characterized by branchial arch anomalies, hearing loss, and kidney defects. Mutations in the human...
BACKGROUND
Branchio-oto-renal (BOR) syndrome is an autosomal-dominant disorder characterized by branchial arch anomalies, hearing loss, and kidney defects. Mutations in the human EYA1 gene have been reported associated with BOR syndrome. Here we identified that a novel variant, EYA1: NM_000503.4: c.827-1G > C (Intron 8, shear mutation) was associated with BOR in a fetus of a Chinese family.
CASE PRESENTATION
Prenatal ultrasound examination showed that both kidneys of the fetus were small and the echo of both kidneys was enhanced. The amount of amniotic fluid was normal, and no other structural abnormalities of the fetus were found. Fetal umbilical cord blood puncture was performed. No abnormality was found in karyotyping and chromosomal microarray analysis (CMA) results. Thus, we performed a trio-based whole exome sequencing (WES), and found that the fetus carried a novel homozygous variant, EYA1: NM_000503.4: c.827-1G > C (Intron 8, shear mutation), but the parents do not have this mutation. The variation sites of fetus and parents were verified by Sanger sequencing to clarify the source of pathogenic variation.
CONCLUSION
Combined with fetal imaging examination, the novel variation of EYA1: NM_000503.4: c.827-1G > C is the cause of fetal renal dysplasia. This case report indicates that the early use of appropriate technology can clarify the etiology of fetal disease and guide prognosis consultation.
Topics: Pregnancy; Female; Humans; Branchio-Oto-Renal Syndrome; Protein Tyrosine Phosphatases; Intracellular Signaling Peptides and Proteins; Pedigree; Nuclear Proteins; Prenatal Diagnosis; Fetus
PubMed: 36316881
DOI: 10.1097/MD.0000000000031172 -
Indian Journal of Otolaryngology and... Sep 2007Branchio-oto-renal syndrome (Melnick-Fraser Syndrome) is a rare Autosomal Dominant disorder characterized by the syndromic association of branchial cysts or fistulae...
Branchio-oto-renal syndrome (Melnick-Fraser Syndrome) is a rare Autosomal Dominant disorder characterized by the syndromic association of branchial cysts or fistulae along with external, middle & inner malformations and renal anomalies. Incomplete penetrance and variable expressivity are common with the phenotypic variation ranging from mild to severe forms & consisting of various eye, ear, oral and craniofacial abnormalities. Mutations in the EYA1 gene on chromosomal site 8q13.3 are identified as the primary cause of BOR syndrome. We present a 3year old child with BOR syndrome, who came to us with bilateral low set, malformed ears & profound cochlear hearing loss along with bilateral branchial fistulae & unilateral renal agenesis. This child underwent successful cochlear implantation recently. The clinical presentation, pre-operative investigations, intra-operative findings & post-op habilitation status are presented with special highlights on the unique facial nerve course along with middle and inner ear anomalies which posed a surgical challenge during cochlear implantation.
PubMed: 23120453
DOI: 10.1007/s12070-007-0081-7 -
BMC Nephrology Aug 2023Branchio-oto-renal (BOR) syndrome is an inherited multi-systemic disorder. Auricular and branchial signs are highly suggestive of BOR syndrome but often develop...
BACKGROUND
Branchio-oto-renal (BOR) syndrome is an inherited multi-systemic disorder. Auricular and branchial signs are highly suggestive of BOR syndrome but often develop insidiously, leading to a remarkable misdiagnosis rate. Unlike severe morphological abnormalities of kidneys, knowledge of glomerular involvement in BOR syndrome were limited.
CASE PRESENTATION
Three cases, aged 8 ~ 9 years, visited pediatric nephrology department mainly for proteinuria and renal insufficiency, with 24-h proteinuria of 23.8 ~ 68.9 mg/kg and estimated glomerular filtration rate of 8.9 ~ 36.0 mL/min/1.73m. Moderate-to-severe albuminuria was detected in case 1, while mixed proteinuria was detected in case 2 and 3. Insidious auricular and branchial fistulas were noticed, all developing since early childhood but being neglected previously. EYA1 variants were confirmed by genetic testing in all cases. Delay in diagnosis was 8 ~ 9 years since extra-renal appearances, and 0 ~ 6 years since renal abnormalities. In case 1, therapy of glucocorticoid and immunosuppressive agents to accompanying immune-complex mediated glomerulonephritis was unsatisfying.
CONCLUSIONS
BOR syndrome is a rare cause of proteinuria and abnormal kidney function and easily missed, thus requiring more awareness. Careful medical history taking and physical examination are essential to early diagnosis. Massive proteinuria was occasionally seen in BOR syndrome, which might be related to immune complex deposits. A novel pathogenic variant (NM_000503.6 (EYA1): c.1171delT p.Ser391fs*9) was firstly reported.
Topics: Child, Preschool; Humans; Child; Branchio-Oto-Renal Syndrome; Renal Insufficiency; Kidney; Proteinuria; Albuminuria; Glomerulonephritis
PubMed: 37612603
DOI: 10.1186/s12882-023-03193-3 -
Proceedings of the National Academy of... May 2004Urinary tract malformations constitute the most frequent cause of chronic renal failure in the first two decades of life. Branchio-otic (BO) syndrome is an autosomal...
Urinary tract malformations constitute the most frequent cause of chronic renal failure in the first two decades of life. Branchio-otic (BO) syndrome is an autosomal dominant developmental disorder characterized by hearing loss. In branchio-oto-renal (BOR) syndrome, malformations of the kidney or urinary tract are associated. Haploinsufficiency for the human gene EYA1, a homologue of the Drosophila gene eyes absent (eya), causes BOR and BO syndromes. We recently mapped a locus for BOR/BO syndrome (BOS3) to human chromosome 14q23.1. Within the 33-megabase critical genetic interval, we located the SIX1, SIX4, and SIX6 genes, which act within a genetic network of EYA and PAX genes to regulate organogenesis. These genes, therefore, represented excellent candidate genes for BOS3. By direct sequencing of exons, we identified three different SIX1 mutations in four BOR/BO kindreds, thus identifying SIX1 as a gene causing BOR and BO syndromes. To elucidate how these mutations cause disease, we analyzed the functional role of these SIX1 mutations with respect to protein-protein and protein-DNA interactions. We demonstrate that all three mutations are crucial for Eya1-Six1 interaction, and the two mutations within the homeodomain region are essential for specific Six1-DNA binding. Identification of SIX1 mutations as causing BOR/BO offers insights into the molecular basis of otic and renal developmental diseases in humans.
Topics: Amino Acid Sequence; Base Sequence; Branchio-Oto-Renal Syndrome; Cell Line; DNA; Gene Expression Regulation, Developmental; Genes, Reporter; Homeodomain Proteins; Humans; Intracellular Signaling Peptides and Proteins; Macromolecular Substances; Molecular Sequence Data; Mutation; Nuclear Proteins; Protein Binding; Protein Structure, Tertiary; Protein Tyrosine Phosphatases; Trans-Activators
PubMed: 15141091
DOI: 10.1073/pnas.0308475101 -
Biochemical Society Transactions Jun 2021The Eyes Absent (EYA) transactivator-phosphatase proteins are important contributors to cell-fate determination processes and to the development of multiple organs. The... (Review)
Review
The Eyes Absent (EYA) transactivator-phosphatase proteins are important contributors to cell-fate determination processes and to the development of multiple organs. The transcriptional regulatory activity as well as the protein tyrosine phosphatase activities of the EYA proteins can independently contribute to proliferation, differentiation, morphogenesis and tissue homeostasis in different contexts. Aberrant EYA levels or activity are associated with numerous syndromic and non-syndromic developmental disorders, as well as cancers. Commensurate with the multiplicity of biochemical activities carried out by the EYA proteins, they impact upon a range of cellular signaling pathways. Here, we provide a broad overview of the roles played by EYA proteins in development, and highlight the molecular signaling pathways known to be linked with EYA-associated organ development and developmental disorders.
Topics: Animals; Congenital Abnormalities; Eye; Gene Expression Regulation, Developmental; Genetic Predisposition to Disease; Humans; Kidney; Mutation; Protein Tyrosine Phosphatases; Trans-Activators
PubMed: 34196366
DOI: 10.1042/BST20201302