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Biology of the Cell Feb 2010The 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...
BACKGROUND INFORMATION
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.
RESULTS
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.
CONCLUSIONS
These studies lend support to the hypothesis that dominant-negative effects of EYA1 mutations may have a role in the pathogenesis of BOR.
Topics: Amino Acid Sequence; Animals; Basic Helix-Loop-Helix Transcription Factors; Branchio-Oto-Renal Syndrome; Disease Models, Animal; Ear; Embryo, Nonmammalian; Eye Proteins; Gene Expression Regulation, Developmental; Homeodomain Proteins; Humans; Intracellular Signaling Peptides and Proteins; Molecular Sequence Data; Mutation; Nerve Tissue Proteins; Nuclear Proteins; Protein Tyrosine Phosphatases; RNA, Messenger; Sequence Alignment; Transcription Factors; Xenopus Proteins; Xenopus laevis
PubMed: 19951260
DOI: 10.1042/BC20090098 -
Frontiers in Immunology 202022q11.2 deletion syndrome (DiGeorge), CHARGE syndrome, Nude/SCID and otofaciocervical syndrome type 2 (OTFCS2) are distinct clinical conditions in humans that can result... (Review)
Review
22q11.2 deletion syndrome (DiGeorge), CHARGE syndrome, Nude/SCID and otofaciocervical syndrome type 2 (OTFCS2) are distinct clinical conditions in humans that can result in hypoplasia and occasionally, aplasia of the thymus. Thymic hypoplasia/aplasia is first suggested by absence or significantly reduced numbers of recent thymic emigrants, revealed in standard-of-care newborn screens for T cell receptor excision circles (TRECs). Subsequent clinical assessments will often indicate whether genetic mutations are causal to the low T cell output from the thymus. However, the molecular mechanisms leading to the thymic hypoplasia/aplasia in diverse human syndromes are not fully understood, partly because the problems of the thymus originate during embryogenesis. Rodent and Zebrafish models of these clinical syndromes have been used to better define the underlying basis of the clinical presentations. Results from these animal models are uncovering contributions of different cell types in the specification, differentiation, and expansion of the thymus. Cell populations such as epithelial cells, mesenchymal cells, endothelial cells, and thymocytes are variably affected depending on the human syndrome responsible for the thymic hypoplasia. In the current review, findings from the diverse animal models will be described in relation to the clinical phenotypes. Importantly, these results are suggesting new strategies for regenerating thymic tissue in patients with distinct congenital disorders.
Topics: Animals; Branchio-Oto-Renal Syndrome; CHARGE Syndrome; DiGeorge Syndrome; Disease Models, Animal; Humans; Immunologic Deficiency Syndromes; Mice; Mutation; Rats; Severe Combined Immunodeficiency; Thymus Gland; Zebrafish
PubMed: 32431714
DOI: 10.3389/fimmu.2020.00830 -
Journal of the Association For Research... Sep 2004Allele variants of EYA1 and EYA4, two members of the vertebrate Eya gene family, underlie two types of inherited human deafness, branchio-oto-renal (BOR) syndrome and... (Comparative Study)
Comparative Study
Allele variants of EYA1 and EYA4, two members of the vertebrate Eya gene family, underlie two types of inherited human deafness, branchio-oto-renal (BOR) syndrome and DFNA10, respectively. To clarify how mutations in these two genes and their encoded proteins impact the normal biology of hearing, we completed a number of functional studies using the yeast-two-hybrid system. We verified that bait constructs of the homologous region ( Eya1HR and Eya4HR) interact with Six1 prey constructs, although no interaction with Dach1 prey was demonstrable. To compare interaction affinities, we evaluated alpha-galactosidase activity after cotransformation of Eya1HR/Six1 and Eya4HR/Six1 and found that the latter interaction was weaker. By immunofluorescence staining, we showed Eya4HR localization to the cytoplasm. After coexpression of Six1, Eya4HR was translocated to the nucleus. Results with Eya1HR were similar. Translation of mutant constructs ( Eya4HR(R564X) and Eya1HR(R539X)) could not be demonstrated. Using dual Eya-containing constructs (with two wild-type alleles or wild-type and mutant alleles), we confirmed no translation of the mutant allele, even if the mutation was nontruncating. These results are consistent with clinical data and implicate haploinsufficiency as the cause of BOR syndrome and DFNA10.
Topics: Animals; Branchio-Oto-Renal Syndrome; COS Cells; Eye Proteins; Gene Expression Regulation, Developmental; Haplotypes; Hearing; Homeodomain Proteins; Humans; Intracellular Signaling Peptides and Proteins; Isomerism; Kidney; Mice; Models, Molecular; Mutagenesis, Site-Directed; Nuclear Proteins; Phenotype; Protein Tyrosine Phosphatases; Structure-Activity Relationship; Trans-Activators; Two-Hybrid System Techniques; Yeasts
PubMed: 15492887
DOI: 10.1007/s10162-004-4044-3 -
Neural Plasticity 2021Branchio-oto-renal spectrum disorder (BORSD) is characterized by hearing loss accompanied by ear malformations, branchial cysts, and fistulae, with (branchio-oto-renal...
Branchio-oto-renal spectrum disorder (BORSD) is characterized by hearing loss accompanied by ear malformations, branchial cysts, and fistulae, with (branchio-oto-renal syndrome (BORS)) or without renal abnormalities (BOS (branchio-otic syndrome)). As the most common causative gene for BORSD, dominant mutations in are responsible for approximately 40% of the cases. In a sporadic deaf patient diagnosed as BOS, we identified an apparent heterozygous genomic deletion spanning the first four coding exons and one 5' noncoding exon of by targeted next-generation sequencing of 406 known deafness genes. Real-time PCR at multiple regions of confirmed the existence of this genomic deletion and extended its 5' boundary beyond the 5'-UTR. Whole genome sequencing subsequently located the 5' and 3' breakpoints to 19268 bp upstream to the ATG initiation codon and 3180 bp downstream to exon 5. PCR amplification across the breakpoints in both the patient and his parents showed that the genomic alteration occurred . Sanger sequencing of this PCR product revealed that it is in fact a GRCh38/hg38:chr8:g.71318554_71374171delinsTGCC genomic deletion-insertion. Our results showed that the genomic variant is responsible for the hearing loss associated with BOS and provided an example for deciphering such cryptic genomic alterations following pipelines of comprehensive exome/genome sequencing and designed verification.
Topics: 5' Untranslated Regions; Branchio-Oto-Renal Syndrome; Child; Codon; Deafness; Exons; Gene Deletion; Hearing Loss; Hearing Loss, Sensorineural; High-Throughput Nucleotide Sequencing; High-Throughput Screening Assays; Humans; Intracellular Signaling Peptides and Proteins; Male; Mutagenesis, Insertional; Nuclear Proteins; Pedigree; Polymerase Chain Reaction; Protein Tyrosine Phosphatases
PubMed: 33880118
DOI: 10.1155/2021/5524381 -
Developmental Dynamics : An Official... Dec 1998Branchio-Oto-Renal (BOR) syndrome is an autosomal dominant, early developmental defect characterised by varying combinations of branchial (fistulas, sinuses, and cysts),...
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. The gene underlying this syndrome, EYA1, is homologous to the Drosophila developmental gene eyes absent which encodes a transcriptional co-activator required for eye specification. We report here the temporal and spatial pattern of expression of the murine homologue, Eya1, throughout ear and kidney development in relation to the anomalies of BOR syndrome. The expression of Eya1 in the branchial arch apparatus (namely in the 2nd, 3rd, and 4th branchial clefts and pharyngeal pouches) at embryonic day (E)10.5, can be correlated with the branchial fistulas, sinuses, and cysts but not with the outer and middle ear anomalies. In contrast, Eya1 is expressed during the slightly more advanced stage of outer and middle ear morphogenesis at E13.5, in the mesenchyme adjacent to the first branchial cleft (the cleft will give rise to the external auditory canal and the surrounding mesenchyme to the auricular hillocks) and surrounding the primordia of the middle ear ossicles, and in the epithelium of the tubotympanic recess (the future tympanic cavity). During early inner ear development, Eya1 is expressed in the ventromedial wall of the otic vesicle (the site of the future sensory epithelia), in the statoacoustic ganglion, and in the periotic mesenchyme, consistent with the cochlear anomalies and sensorineural hearing loss of BOR syndrome. Subsequently, Eya1 expression is observed in the differentiating hair and supporting cells of the sensory epithelia, as well as in the associated ganglia, and persists after differentiation has taken place. This suggests that, in addition to a role in the morphogenetic process, Eya1 could also be implicated in the differentiation and/or survival of these inner ear cell populations. Finally, Eya1 expression in the condensing mesenchymal cells of the kidney is consistent with the excretory and collecting system anomalies of BOR syndrome. From the comparison of the Eya1 and Pax2 expression patterns during ear and kidney development, a contribution of these two genes to the same regulatory pathway can only be suggested in the mesenchymal-epithelial transition directing renal tubule formation.
Topics: Animals; Branchial Region; Branchio-Oto-Renal Syndrome; Cochlea; Disease Models, Animal; Ear; Ear, External; Ear, Inner; Ear, Middle; Gene Expression; Intracellular Signaling Peptides and Proteins; Kidney; Mice; Nuclear Proteins; Protein Tyrosine Phosphatases; Trans-Activators; Vestibule, Labyrinth
PubMed: 9853969
DOI: 10.1002/(SICI)1097-0177(199812)213:4<486::AID-AJA13>3.0.CO;2-L -
Branchio-oculo-facial syndrome and branchio-otic/branchio-oto-renal syndromes are distinct entities.Journal of Medical Genetics Jan 2002
Comparative Study
Topics: Abnormalities, Multiple; Branchio-Oto-Renal Syndrome; Cleft Lip; Craniofacial Abnormalities; Eye Abnormalities; Female; Hearing Loss, Sensorineural; Humans; Male; Pedigree; Skin Abnormalities; Syndrome
PubMed: 11826031
DOI: 10.1136/jmg.39.1.71 -
Zhongguo Dang Dai Er Ke Za Zhi =... Jun 2022Microtia is the second most common maxillofacial birth defect in neonates and has an prevalence rate of 3.06/10 000 in China, and 20%-60% of microtia cases is associated...
Microtia is the second most common maxillofacial birth defect in neonates and has an prevalence rate of 3.06/10 000 in China, and 20%-60% of microtia cases is associated with a certain type of syndrome. This article elaborates on the clinical phenotypes and genetic characteristics of three microtia-associated syndromes (MASs) with high prevalence, high incidence rate of ear deformity, and definite genetic etiology, i.e., oculo-auriculo-vertebral spectrum, branchio-oto-renal spectrum disorder, and Treacher-Collins syndrome, and summarizes another three common MASs, so as to provide a reference for the genetic diagnosis of neonatal MAS.
Topics: China; Congenital Microtia; Humans; Infant, Newborn; Phenotype; Prevalence; Syndrome
PubMed: 35762425
DOI: 10.7499/j.issn.1008-8830.2203008 -
Journal of Medical Genetics Oct 1995A sporadic patient with OFC syndrome is described. Distinguishing features were a long face with narrow nose, high arched palate, prominent and dysmorphic ears, long...
A sporadic patient with OFC syndrome is described. Distinguishing features were a long face with narrow nose, high arched palate, prominent and dysmorphic ears, long neck, sloping shoulders and clavicles, winged, low, and laterally set scapulae, tetralogy of Fallot, and deafness secondary to cochlear malformation. Some features present in the original family, including lateral cervical fistulae, have suggested that OFC syndrome could be a variant of BOR syndrome. The absence of preauricular tags, lacrimal duct stenosis, and renal malformations, and the presence of distinct facial and radiographic findings and markedly downward sloping shoulders in the present patient support OFC syndrome being a unique, clinically recognisable entity.
Topics: Abnormalities, Multiple; Adolescent; Branchial Region; Cervical Vertebrae; Chromosomes, Human, Pair 22; Chromosomes, Human, Pair 8; Ear; Face; Female; Fingers; Hearing Disorders; Humans; Shoulder; Syndrome; Tomography Scanners, X-Ray Computed
PubMed: 8558563
DOI: 10.1136/jmg.32.10.816 -
American Journal of Medical Genetics.... Nov 2010Branchio-oto-renal syndrome is characterized by branchial defects, hearing loss, preauricular pits, and renal anomalies. Mutations in EYA1 are the most common cause of...
Branchio-oto-renal syndrome is characterized by branchial defects, hearing loss, preauricular pits, and renal anomalies. Mutations in EYA1 are the most common cause of branchio-oto-renal and branchio-otic syndromes. Large chromosomal aberrations of 8q13, including complex rearrangements occur in about 20% of these individuals. However, submicroscopic deletions and the molecular characterization of genomic rearrangements involving the EYA1 gene have rarely been reported. Using the array-comparative genomic hybridization, we identified non-recurrent genomic deletions including the EYA1 gene in three patients with branchio-oto-renal syndrome, short stature, and developmental delay. One of these deletions was mediated by two human endogenous retroviral sequence blocks, analogous to the AZFa microdeletion on Yq11, responsible for male infertility. This report describes the expanded phenotype of individuals, resulting from contiguous gene deletion involving the EYA1 gene and provides a molecular description of the genomic rearrangements involving this gene in branchio-oto-renal syndrome.
Topics: Branchio-Oto-Renal Syndrome; Child; Child, Preschool; Chromosome Deletion; Comparative Genomic Hybridization; Endogenous Retroviruses; Female; Gene Deletion; Gene Rearrangement; Genome, Human; Humans; Infant; Infant, Newborn; Intracellular Signaling Peptides and Proteins; Male; Nuclear Proteins; Pregnancy; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Protein Tyrosine Phosphatases
PubMed: 20979191
DOI: 10.1002/ajmg.a.33686 -
ORL; Journal For Oto-rhino-laryngology... 2006Understanding the genetic basis of hearing loss is important because almost 50% of profound hearing loss are caused by genetic factors and more than 120 independent... (Review)
Review
Understanding the genetic basis of hearing loss is important because almost 50% of profound hearing loss are caused by genetic factors and more than 120 independent genes have been identified. In this review, after a brief explanation of some genetic terms (allele, heterozygosis, homozygosis, polymorphism, genotype and phenotype), classification of genetic hearing loss (syndromic versus nonsyndromic, and recessive dominant, X-linked and mitochondrial) was performed. Some of the most common syndromes (Usher, Pendred, Jervell and Lange-Nielsen, Waardenburg, branchio-oto-renal, Stickler, Treacher Collins and Alport syndromes, biotinidase deficiency and Norrie disease) causing genetic hearing loss were also explained briefly. The genes involved in hearing loss and genetic heterogeneity were presented.
Topics: Alleles; DNA, Mitochondrial; Genetic Heterogeneity; Genotype; Hearing Loss; Humans; Inheritance Patterns; Phenotype; Polymorphism, Genetic; Syndrome
PubMed: 16428895
DOI: 10.1159/000091090