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BMC Medical Genomics Apr 2024Branchio-oto-renal syndrome (BOR, OMIM#113,650) is a rare autosomal dominant disorder that presents with a variety of symptoms, including hearing loss (sensorineural,...
OBJECTIVE
Branchio-oto-renal syndrome (BOR, OMIM#113,650) is a rare autosomal dominant disorder that presents with a variety of symptoms, including hearing loss (sensorineural, conductive, or mixed), structural abnormalities affecting the outer, middle, and inner ear, branchial fistulas or cysts, as well as renal abnormalities.This study aims to identify the pathogenic variants by performing genetic testing on a family with Branchio-oto-renal /Branchio-otic (BO, OMIM#602,588) syndrome using whole-exome sequencing, and to explore possible pathogenic mechanisms.
METHODS
The family spans 4 generations and consists of 9 individuals, including 4 affected by the BOR/BO syndrome. Phenotypic information, including ear malformation and branchial cleft, was collected from family members. Audiological, temporal bone imaging, and renal ultrasound examinations were also performed. Whole-exome sequencing was conducted to identify candidate pathogenic variants and explore the underlying molecular etiology of BOR/BO syndrome by minigene experiments.
RESULTS
Intra-familial variability was observed in the clinical phenotypes of BOR/BO syndrome in this family. The severity and nature of hearing loss varied in family members, with mixed or sensorineural hearing loss. The proband, in particular, had profound sensorineural hearing loss on the left and moderate conductive hearing loss on the right. Additionally, the proband exhibited developmental delay, and her mother experienced renal failure during pregnancy and terminated the pregnancy prematurely. Genetic testing revealed a novel heterozygous variant NM_000503.6: c.639 + 3 A > C in the EYA1 gene in affected family members. In vitro minigene experiments demonstrated its effect on splicing. According to the American College of Medical Genetics (ACMG) guidelines, this variant was classified as likely pathogenic.
CONCLUSION
This study highlights the phenotypic heterogeneity within the same family, reports the occurrence of renal failure and adverse pregnancy outcomes in a female patient at reproductive age with BOR syndrome, and enriches the mutational spectrum of pathogenic variants in the EYA1 gene.
Topics: Humans; Pregnancy; Female; Branchio-Oto-Renal Syndrome; Intracellular Signaling Peptides and Proteins; Protein Tyrosine Phosphatases; Hearing Loss; Deafness; Hearing Loss, Sensorineural; Renal Insufficiency; Pedigree; Nuclear Proteins
PubMed: 38627775
DOI: 10.1186/s12920-024-01858-y -
Balkan Journal of Medical Genetics :... Dec 2016Branchio-oto-renal (BOR) syndrome is an autosomal dominant disorder characterized by the coexistence of branchial cysts or fistulae, external ear malformation with...
Branchio-oto-renal (BOR) syndrome is an autosomal dominant disorder characterized by the coexistence of branchial cysts or fistulae, external ear malformation with pre-auricular pits or tags, hearing impairment and renal malformations. However, the presence of the main features varies in affected families. Here, we present a 16-year-old boy admitted to the Department of Nephrology at the Pediatric Clinic, University Clinical Center of Kosovo, Pristina, Republic of Kosovo because of severe renal insufficiency diagnosed 6 years ago, which progressed to end-stage renal failure. Clinical examination on readmission showed a pale, lethargic and edematous child, with auricular deformity, pre-auricular tags and pits as well as bilateral branchial fistulae. Laboratory tests revealed high blood urea nitrogen (BUN) 15.96 mmol/L and serum creatinine 633.0 µmol/L; low glomerular filtration rate (GFR) 12 mL/min./ 1.73 m and massive proteinuria 4+. Abdominal ultrasound showed bilateral kidney hypoplasia. A novel mutation of the gene was confirmed. Daily hemodialysis is continuing until renal transplantation is done. This case is presented to increase awareness among general practitioners to consider BOR syndrome or other renal abnormalities in patients with branchial fistula and/ or external ear anomalies or similar findings in other family members.
PubMed: 28289595
DOI: 10.1515/bjmg-2016-0042 -
Development (Cambridge, England) May 2023Developmental senescence is a form of programmed senescence that contributes to morphogenesis during embryonic development. We showed recently that the SIX1...
Developmental senescence is a form of programmed senescence that contributes to morphogenesis during embryonic development. We showed recently that the SIX1 homeoprotein, an essential regulator of organogenesis, is also a repressor of adult cellular senescence. Alterations in the SIX/EYA pathway are linked to the human branchio-oto-renal (BOR) syndrome, a rare congenital disorder associated with defects in the ears, kidneys and branchial arches. Here, we have used Six1-deficient mice, an animal model of the BOR syndrome, to investigate whether dysfunction of senescence underpins the developmental defects associated with SIX1 deficiency. We have focused on the developing inner ear, an organ with physiological developmental senescence that is severely affected in Six1-deficient mice and BOR patients. We show aberrant levels and distribution of senescence markers in Six1-deficient inner ears concomitant with defective morphogenesis of senescent structures. Transcriptomic analysis and ex vivo assays support a link between aberrant senescence and altered morphogenesis in this model, associated with deregulation of the TGFβ/BMP pathway. Our results show that misregulation of embryo senescence may lead to genetic developmental disorders, significantly expanding the connection between senescence and disease.
Topics: Adult; Humans; Mice; Animals; Protein Tyrosine Phosphatases; Intracellular Signaling Peptides and Proteins; Nuclear Proteins; Ear, Inner; Branchio-Oto-Renal Syndrome; Homeodomain Proteins
PubMed: 37017267
DOI: 10.1242/dev.200903 -
Developmental Biology Sep 2022Mcrs1 is a multifunctional protein that is critical for many cellular processes in a wide range of cell types. Previously, we showed that Mcrs1 binds to the Six1...
Mcrs1 is a multifunctional protein that is critical for many cellular processes in a wide range of cell types. Previously, we showed that Mcrs1 binds to the Six1 transcription factor and reduces the ability of the Six1-Eya1 complex to upregulate transcription, and that Mcrs1 loss-of-function leads to the expansion of several neural plate genes, reduction of neural border and pre-placodal ectoderm (PPR) genes, and pleiotropic effects on various neural crest (NC) genes. Because the affected embryonic structures give rise to several of the cranial tissues affected in Branchio-otic/Branchio-oto-renal (BOR) syndrome, herein we tested whether these gene expression changes subsequently alter the development of the proximate precursors of BOR affected structures - the otic vesicles (OV) and branchial arches (BA). We found that Mcrs1 is required for the expression of several OV genes involved in inner ear formation, patterning and otic capsule cartilage formation. Mcrs1 knockdown also reduced the expression domains of many genes expressed in the larval BA, derived from either NC or PPR, except for emx2, which was expanded. Reduced Mcrs1 also diminished the length of the expression domain of tbx1 in BA1 and BA2 and interfered with cranial NC migration from the dorsal neural tube; this subsequently resulted in defects in the morphology of lower jaw cartilages derived from BA1 and BA2, including the infrarostral, Meckel's, and ceratohyal as well as the otic capsule. These results demonstrate that Mcrs1 plays an important role in processes that lead to the formation of craniofacial cartilages and its loss results in phenotypes consistent with reduced Six1 activity associated with BOR.
Topics: Branchial Region; Branchio-Oto-Renal Syndrome; Cartilage; Gene Expression Regulation, Developmental; Homeodomain Proteins; Neural Crest; Neural Plate; RNA-Binding Proteins
PubMed: 35697116
DOI: 10.1016/j.ydbio.2022.06.002 -
The Journal of Biological Chemistry Jul 2009Branchio-oto-renal syndrome (BOR) is an autosomal dominant developmental disorder characterized by hearing loss, branchial arch defects, and renal anomalies. Recently,...
Branchio-oto-renal syndrome (BOR) is an autosomal dominant developmental disorder characterized by hearing loss, branchial arch defects, and renal anomalies. Recently, eight mutations in the SIX1 homeobox gene were discovered in BOR patients. To characterize the effect of SIX1 BOR mutations on the EYA-SIX1-DNA complex, we expressed and purified six of the eight mutants in Escherichia coli. We demonstrate that only the most N-terminal mutation in SIX1 (V17E) completely abolishes SIX1-EYA complex formation, whereas all of the other mutants are able to form a stable complex with EYA. We further show that only the V17E mutant fails to localize EYA to the nucleus and cannot be stabilized by EYA in the cell. The remaining five SIX1 mutants are instead all deficient in DNA binding. In contrast, V17E alone has a DNA binding affinity similar to that of wild type SIX1 in complex with the EYA co-factor. Finally, we show that all SIX1 BOR mutants are defective in transcriptional activation using luciferase reporter assays. Taken together, our experiments demonstrate that the SIX1 BOR mutations contribute to the pathology of the disease through at least two different mechanisms that involve: 1) abolishing the formation of the SIX1-EYA complex or 2) diminishing the ability of SIX1 to bind DNA. Furthermore, our data demonstrate for the first time that EYA: 1) requires the N-terminal region of the SIX1 Six domain for its interaction, 2) increases the level of the SIX1 protein within the cell, and 3) increases the DNA binding affinity of SIX1.
Topics: Amino Acid Substitution; Branchio-Oto-Renal Syndrome; Cell Line, Tumor; Cell Nucleus; DNA; Homeodomain Proteins; Humans; Intracellular Signaling Peptides and Proteins; Mutant Proteins; Mutation; Nuclear Proteins; Promoter Regions, Genetic; Protein Binding; Protein Stability; Protein Structure, Secondary; Protein Structure, Tertiary; Protein Transport; Protein Tyrosine Phosphatases; Transcriptional Activation
PubMed: 19497856
DOI: 10.1074/jbc.M109.016832 -
FEBS Letters Jul 2006The Eyes Absent (Eya) proteins are tyrosine phosphatases and transcriptional activators involved in cell-fate determination and organ development. Mutations in the gene...
The Eyes Absent (Eya) proteins are tyrosine phosphatases and transcriptional activators involved in cell-fate determination and organ development. Mutations in the gene encoding Eya homologue 1 have been implicated in the multi-organ developmental disorder branchio-oto-renal syndrome (BOR) and in ocular defects. Here we report that BOR-associated mutations lead to a loss of phosphatase activity in Eya1 proteins, while mutations associated with ocular defects yield Eya1 proteins with near normal levels of phosphatase activity. Furthermore we demonstrate that the N-terminal domain attenuates the catalytic activity of Eya suggesting a mechanism of regulation.
Topics: Amino Acid Sequence; Amino Acid Substitution; Animals; Branchio-Oto-Renal Syndrome; Catalysis; DNA-Binding Proteins; Humans; Intracellular Signaling Peptides and Proteins; Mice; Models, Molecular; Molecular Sequence Data; Mutation; Nuclear Proteins; Phosphoric Monoester Hydrolases; Protein Tyrosine Phosphatases; Sequence Alignment; Sequence Deletion; Structural Homology, Protein; Substrate Specificity
PubMed: 16797546
DOI: 10.1016/j.febslet.2006.06.009 -
Journal of Pediatric Genetics Mar 2018Congenital hearing loss is one of the most common birth defects worldwide, with around 1 in 500 people experiencing some form of severe hearing loss. While over 400... (Review)
Review
Congenital hearing loss is one of the most common birth defects worldwide, with around 1 in 500 people experiencing some form of severe hearing loss. While over 400 different syndromes involving hearing loss have been described, it is important to be familiar with a wide range of syndromes involving hearing loss so an early diagnosis can be made and early intervention can be pursued to maximize functional hearing and speech-language development in the setting of verbal communication. This review aims to describe the presentation and genetics for some of the most frequently occurring syndromes involving hearing loss, including neurofibromatosis type 2, branchio-oto-renal syndrome, Treacher Collins syndrome, Stickler syndrome, Waardenburg syndrome, Pendred syndrome, Jervell and Lange-Nielsen syndrome, Usher syndromes, Refsum disease, Alport syndrome, MELAS, and MERRF.
PubMed: 29441214
DOI: 10.1055/s-0037-1617454 -
International Braz J Urol : Official... 2022To evaluate the anatomical aspects of the kidney surface in human fetuses during the second gestational trimester.
OBJECTIVE
To evaluate the anatomical aspects of the kidney surface in human fetuses during the second gestational trimester.
MATERIAL AND METHODS
We studied 108 kidneys obtained from 54 human fetuses (29 males and 25 females). The kidney was dissected and the number of clefts was counted. The renal volume was also assessed. To compare the quantitative data in both sexes, the Students-t-test was used (p < 0.05). Simple linear correlations were calculated for all kidney measurements, according to fetal age. Statistical analysis was performed with the R program (Version 3.5.1).
RESULTS
The fetuses ranged in age between 11.4 to 23 weeks post-conception. The renal volume of the right kidney ranged from 0.09 to 2.397 cm (mean=0.8479) and the renal volume of the left kidney ranged from 0.07 to 2.416 cm (mean=0.8036). The mean number of renal clefts in fetuses studied was 15.25 (7 to 28). There was no statistical significant difference in renal clefts between the sides either in males (p = 0.646) or in females (p = 0.698). Also, there was no significant difference in the mean number of renal clefts between male and female fetuses in right kidney (p = 0.948) and in left kidney (p = 0.939).
CONCLUSIONS
The number of renal clefts has a great variation, weak correlation and no tendency to decrease during the 2nd gestational trimester. The number of clefts in right kidney of total sample and female fetuses has a significant development with age.
Topics: Female; Fetus; Gestational Age; Humans; Infant; Kidney; Male; Pregnancy; Pregnancy Trimester, Second
PubMed: 36083266
DOI: 10.1590/S1677-5538.IBJU.2022.9977 -
Medicine Jun 2021Branchio-Oto (BO) syndrome is one of the common syndromic forms of hearing loss. In this study, we aimed to characterize the clinical and genetic features of BO syndrome...
Branchio-Oto (BO) syndrome is one of the common syndromic forms of hearing loss. In this study, we aimed to characterize the clinical and genetic features of BO syndrome in a Chinese deaf family.The proposita in this study was a 29-years-old Chinese female with hearing loss, microtia, anterior concave auricle, and right branchial fistula. The family members agreed to undergo clinical examination. We collected blood samples from 7 family members, including 4 affected by the syndrome. Genomic DNA was extracted and subjected to Sanger sequencing. In addition, bioinformatics software SWISS MODEL was used to predict the protein encoded by EYA transcriptional coactivator and phosphatase 1 (EYA1) gene.Intra-familial consistency can be observed in the clinical phenotypes of BO syndrome in this family. EYA1 c.1627C>T (p.Gln543Ter) mutation was identified as the pathogenic cause in this family.This study reports a mutation associated with BO syndrome in a Chinese Han family. We highlight the utility of genetic testing in the diagnosis of BO syndrome. Thus, we believe that this report would provide a basis for the diagnosis of similar diseases in the future.
Topics: Adult; Aged; Asian People; Audiometry; Branchio-Oto-Renal Syndrome; Child; Computational Biology; Congenital Microtia; DNA Mutational Analysis; Female; Genetic Testing; Hearing Loss; Humans; Intracellular Signaling Peptides and Proteins; Karyotyping; Male; Middle Aged; Nuclear Proteins; Pedigree; Protein Tyrosine Phosphatases
PubMed: 34160378
DOI: 10.1097/MD.0000000000024691 -
The Israel Medical Association Journal... Nov 2007
Review
Topics: Antineoplastic Agents; Branchio-Oto-Renal Syndrome; Carrier Proteins; Cisplatin; Comorbidity; Diuretics; Furosemide; Hearing Disorders; Hearing Loss, Sensorineural; Humans; Kidney Diseases; Nephritis, Hereditary; Renal Insufficiency, Chronic; Tight Junctions
PubMed: 18085042
DOI: No ID Found