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William J. Kimberling - One of the best experts on this subject based on the ideXlab platform.
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six1 mutation screening in 247 branchio oto renal Syndrome families a recurrent missense mutation associated with bor
Human Mutation, 2008Co-Authors: Amit Kochhar, Cor W. R. J. Cremers, William J. Kimberling, Stephanie M Fischer, Dana J. Orten, Jessica L. Sorensen, Richard J.h. SmithAbstract:Branchio-Oto-Renal Syndrome (BOR) is a clinically heterogeneous autosomal dominant form of syndromic hearing loss characterized by variable hearing impairment, malformations of the pinnae, the presence of branchial arch remnants, and various renal abnormalities. Both EYA1 and SIX1 are expressed in developing otic, branchial and renal tissue. Consistent with this expression pattern, mutations in both genes cause BOR Syndrome. Mutations in EYA1 are found in approximately 40% of patients with the BOR phenotype, however, the role of SIX1 is much lower. To date only three different SIX1 mutations have been described in BOR patients. The current screen of 247 BOR families detected five novel SIX1 mutations (c.50T>A, c.218A>C, c.317T>G, c.329G>A, c.334C>T) and one previously reported mutation (c.328C>T) seen in 5 unrelated families. All mutations are within the protein-binding Six domain. Phenotypic variability was high in these BOR families. Seven of the eight known SIX1 mutations are missense and the one in frame deletion is predicted to be functionally similar. The wide phenotypic variability precludes making genotype-phenotype correlations at this time.
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Branchio-Oto-Renal Syndrome (BOR): novel mutations in the EYA1 gene, and a review of the mutational genetics of BOR.
Human Mutation, 2008Co-Authors: Dana J. Orten, Richard J.h. Smith, Cor W. R. J. Cremers, Guy Van Camp, Stephanie M Fischer, Jessica L. Sorensen, Henri A. M. Marres, Uppala Radhakrishna, Katherine O. Welch, William J. KimberlingAbstract:Branchio-Oto-Renal Syndrome (BOR) is an autosomal dominant disorder characterized by the association of branchial and external ear malformations, hearing loss, and renal anomalies. The phenotype varies from ear pits to profound hearing loss, branchial fistulae, and kidney agenesis. The most common gene mutated in BOR families is EYA1, a transcriptional activator. Over 80 different disease-causing mutations have been published (www.healthcare.uiowa.edu/labs/pendredandbor/, last accessed 20 November 2007). We analyzed the EYA1 coding region (16 exons) from 435 families (345 at the University of Iowa [UI] and 95 at Boys Town National Research Hospital [BTNRH], including five at both) and found 70 different EYA1 mutations in 89 families. Most of the mutations (56/70) were private. EYA1 mutations were found in 31% of families (76/248) fitting established clinical criteria for BOR and 7% of families with questionable BOR phenotype (13/187). Severity of the phenotype did not correlate with type of mutation nor with the domain involved. These results add considerably to the spectrum of EYA1 mutations associated with BOR and indicate that the BOR phenotype is an indication for molecular studies to diagnose EYA1-associated BOR.
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SIX1 Mutation Screening in 247 Branchio-Oto-Renal Syndrome Families: A Recurrent Missense Mutation
2008Co-Authors: Amit Kochhar, Richard J.h. Smith, Cor W. R. J. Cremers, William J. Kimberling, Stephanie M Fischer, Dana J. Orten, Jessica L. Sorensen, Doris DukeAbstract:Branchio-Oto-Renal Syndrome (BOR; MIM# 113650) is a clinically heterogeneous autosomal dominant form of syndromic hearing loss characterized by variable hearing impairment, malformations of the pinnae, the presence of branchial arch remnants, and various renal abnormalities. BOR Syndrome is one of the more common autosomal dominant forms of syndromic hearing impairment. It has an estimated incidence of 1:40,000 and affects 2% of profoundly deaf children (Fraser et al., 1980). Hearing loss is present in greater than 70% of affected individuals
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Branchio-Oto-Renal Syndrome.
American Journal of Medical Genetics Part A, 2007Co-Authors: Amit Kochhar, William J. Kimberling, Stephanie M Fischer, Richard J.h. SmithAbstract:Branchio-Oto-Renal Syndrome, a phenotype consisting of hearing loss, auricular malformations, branchial arch remnants, and renal anomalies is now recognized as one of the more common forms of autosomal dominant syndromic hearing impairment. Three loci known to be associated with the BOR phenotype have been identified and two genes that act in a regulatory network have been cloned, EYA1 and SIX1. EYA1 and SIX1 are homologous to genes involved in Drosophila eye development, eyes absent gene (eya), and sine oculis (so), respectively. EYA1, a transcriptional co-activator has a conserved, 271-amino acid, C-terminal known as the Eya Domain (ED). SIX1 has two highly conserved domains; a homeodomain (HD) and a specific Six-domain (SD) whose products function as transcription factors with specific DNA-binding activity that are crucial for protein-protein interaction. To determine the molecular basis for the organ defects that occur in BOR Syndrome, many studies have focused on the effects of mutations to EYA and effects of mutations of the EYA-SIX regulatory system. However, over 60% of BOR Syndrome patients do not have known mutations in EYA1 and relatively little is known about mutations to SIX1. Further evaluation of SIX1 and its related target genes may provide a better understanding of the pathophysiology of BOR Syndrome and offer greater clues to the disease mechanisms.
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Transcription Factor SIX5 Is Mutated in Patients with Branchio-Oto-Renal Syndrome
The American Journal of Human Genetics, 2007Co-Authors: Bethan E. Hoskins, Derek Silvius, Richard M. Raymond, Richard J.h. Smith, William J. Kimberling, Dana J. Orten, Carl H. Cramer, Dan Zou, Dominique Weil, Christine PetitAbstract:Branchio-Oto-Renal Syndrome (BOR) is an autosomal dominant developmental disorder characterized by the association of branchial arch defects, hearing loss, and renal anomalies. Mutations in EYA1 are known to cause BOR. More recently, mutations in SIX1, which interacts with EYA1, were identified as an additional cause of BOR. A second member of the SIX family of proteins, unc-39 (SIX5), has also been reported to directly interact with eya-1 in Caenorhabditis elegans. We hypothesized that this interaction would be conserved in humans and that interactors of EYA1 represent good candidate genes for BOR. We therefore screened a cohort of 95 patients with BOR for mutations in SIX5. Four different heterozygous missense mutations were identified in five individuals. Functional analyses of these mutations demonstrated that two mutations affect EYA1-SIX5 binding and the ability of SIX5 or the EYA1-SIX5 complex to activate gene transcription. We thereby identified heterozygous mutations in SIX5 as a novel cause of BOR.
Richard J.h. Smith - One of the best experts on this subject based on the ideXlab platform.
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six1 mutation screening in 247 branchio oto renal Syndrome families a recurrent missense mutation associated with bor
Human Mutation, 2008Co-Authors: Amit Kochhar, Cor W. R. J. Cremers, William J. Kimberling, Stephanie M Fischer, Dana J. Orten, Jessica L. Sorensen, Richard J.h. SmithAbstract:Branchio-Oto-Renal Syndrome (BOR) is a clinically heterogeneous autosomal dominant form of syndromic hearing loss characterized by variable hearing impairment, malformations of the pinnae, the presence of branchial arch remnants, and various renal abnormalities. Both EYA1 and SIX1 are expressed in developing otic, branchial and renal tissue. Consistent with this expression pattern, mutations in both genes cause BOR Syndrome. Mutations in EYA1 are found in approximately 40% of patients with the BOR phenotype, however, the role of SIX1 is much lower. To date only three different SIX1 mutations have been described in BOR patients. The current screen of 247 BOR families detected five novel SIX1 mutations (c.50T>A, c.218A>C, c.317T>G, c.329G>A, c.334C>T) and one previously reported mutation (c.328C>T) seen in 5 unrelated families. All mutations are within the protein-binding Six domain. Phenotypic variability was high in these BOR families. Seven of the eight known SIX1 mutations are missense and the one in frame deletion is predicted to be functionally similar. The wide phenotypic variability precludes making genotype-phenotype correlations at this time.
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Branchio-Oto-Renal Syndrome (BOR): novel mutations in the EYA1 gene, and a review of the mutational genetics of BOR.
Human Mutation, 2008Co-Authors: Dana J. Orten, Richard J.h. Smith, Cor W. R. J. Cremers, Guy Van Camp, Stephanie M Fischer, Jessica L. Sorensen, Henri A. M. Marres, Uppala Radhakrishna, Katherine O. Welch, William J. KimberlingAbstract:Branchio-Oto-Renal Syndrome (BOR) is an autosomal dominant disorder characterized by the association of branchial and external ear malformations, hearing loss, and renal anomalies. The phenotype varies from ear pits to profound hearing loss, branchial fistulae, and kidney agenesis. The most common gene mutated in BOR families is EYA1, a transcriptional activator. Over 80 different disease-causing mutations have been published (www.healthcare.uiowa.edu/labs/pendredandbor/, last accessed 20 November 2007). We analyzed the EYA1 coding region (16 exons) from 435 families (345 at the University of Iowa [UI] and 95 at Boys Town National Research Hospital [BTNRH], including five at both) and found 70 different EYA1 mutations in 89 families. Most of the mutations (56/70) were private. EYA1 mutations were found in 31% of families (76/248) fitting established clinical criteria for BOR and 7% of families with questionable BOR phenotype (13/187). Severity of the phenotype did not correlate with type of mutation nor with the domain involved. These results add considerably to the spectrum of EYA1 mutations associated with BOR and indicate that the BOR phenotype is an indication for molecular studies to diagnose EYA1-associated BOR.
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SIX1 Mutation Screening in 247 Branchio-Oto-Renal Syndrome Families: A Recurrent Missense Mutation
2008Co-Authors: Amit Kochhar, Richard J.h. Smith, Cor W. R. J. Cremers, William J. Kimberling, Stephanie M Fischer, Dana J. Orten, Jessica L. Sorensen, Doris DukeAbstract:Branchio-Oto-Renal Syndrome (BOR; MIM# 113650) is a clinically heterogeneous autosomal dominant form of syndromic hearing loss characterized by variable hearing impairment, malformations of the pinnae, the presence of branchial arch remnants, and various renal abnormalities. BOR Syndrome is one of the more common autosomal dominant forms of syndromic hearing impairment. It has an estimated incidence of 1:40,000 and affects 2% of profoundly deaf children (Fraser et al., 1980). Hearing loss is present in greater than 70% of affected individuals
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Branchio-Oto-Renal Syndrome.
American Journal of Medical Genetics Part A, 2007Co-Authors: Amit Kochhar, William J. Kimberling, Stephanie M Fischer, Richard J.h. SmithAbstract:Branchio-Oto-Renal Syndrome, a phenotype consisting of hearing loss, auricular malformations, branchial arch remnants, and renal anomalies is now recognized as one of the more common forms of autosomal dominant syndromic hearing impairment. Three loci known to be associated with the BOR phenotype have been identified and two genes that act in a regulatory network have been cloned, EYA1 and SIX1. EYA1 and SIX1 are homologous to genes involved in Drosophila eye development, eyes absent gene (eya), and sine oculis (so), respectively. EYA1, a transcriptional co-activator has a conserved, 271-amino acid, C-terminal known as the Eya Domain (ED). SIX1 has two highly conserved domains; a homeodomain (HD) and a specific Six-domain (SD) whose products function as transcription factors with specific DNA-binding activity that are crucial for protein-protein interaction. To determine the molecular basis for the organ defects that occur in BOR Syndrome, many studies have focused on the effects of mutations to EYA and effects of mutations of the EYA-SIX regulatory system. However, over 60% of BOR Syndrome patients do not have known mutations in EYA1 and relatively little is known about mutations to SIX1. Further evaluation of SIX1 and its related target genes may provide a better understanding of the pathophysiology of BOR Syndrome and offer greater clues to the disease mechanisms.
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Transcription Factor SIX5 Is Mutated in Patients with Branchio-Oto-Renal Syndrome
The American Journal of Human Genetics, 2007Co-Authors: Bethan E. Hoskins, Derek Silvius, Richard M. Raymond, Richard J.h. Smith, William J. Kimberling, Dana J. Orten, Carl H. Cramer, Dan Zou, Dominique Weil, Christine PetitAbstract:Branchio-Oto-Renal Syndrome (BOR) is an autosomal dominant developmental disorder characterized by the association of branchial arch defects, hearing loss, and renal anomalies. Mutations in EYA1 are known to cause BOR. More recently, mutations in SIX1, which interacts with EYA1, were identified as an additional cause of BOR. A second member of the SIX family of proteins, unc-39 (SIX5), has also been reported to directly interact with eya-1 in Caenorhabditis elegans. We hypothesized that this interaction would be conserved in humans and that interactors of EYA1 represent good candidate genes for BOR. We therefore screened a cohort of 95 patients with BOR for mutations in SIX5. Four different heterozygous missense mutations were identified in five individuals. Functional analyses of these mutations demonstrated that two mutations affect EYA1-SIX5 binding and the ability of SIX5 or the EYA1-SIX5 complex to activate gene transcription. We thereby identified heterozygous mutations in SIX5 as a novel cause of BOR.
Cor W. R. J. Cremers - One of the best experts on this subject based on the ideXlab platform.
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six1 mutation screening in 247 branchio oto renal Syndrome families a recurrent missense mutation associated with bor
Human Mutation, 2008Co-Authors: Amit Kochhar, Cor W. R. J. Cremers, William J. Kimberling, Stephanie M Fischer, Dana J. Orten, Jessica L. Sorensen, Richard J.h. SmithAbstract:Branchio-Oto-Renal Syndrome (BOR) is a clinically heterogeneous autosomal dominant form of syndromic hearing loss characterized by variable hearing impairment, malformations of the pinnae, the presence of branchial arch remnants, and various renal abnormalities. Both EYA1 and SIX1 are expressed in developing otic, branchial and renal tissue. Consistent with this expression pattern, mutations in both genes cause BOR Syndrome. Mutations in EYA1 are found in approximately 40% of patients with the BOR phenotype, however, the role of SIX1 is much lower. To date only three different SIX1 mutations have been described in BOR patients. The current screen of 247 BOR families detected five novel SIX1 mutations (c.50T>A, c.218A>C, c.317T>G, c.329G>A, c.334C>T) and one previously reported mutation (c.328C>T) seen in 5 unrelated families. All mutations are within the protein-binding Six domain. Phenotypic variability was high in these BOR families. Seven of the eight known SIX1 mutations are missense and the one in frame deletion is predicted to be functionally similar. The wide phenotypic variability precludes making genotype-phenotype correlations at this time.
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Branchio-Oto-Renal Syndrome (BOR): novel mutations in the EYA1 gene, and a review of the mutational genetics of BOR.
Human Mutation, 2008Co-Authors: Dana J. Orten, Richard J.h. Smith, Cor W. R. J. Cremers, Guy Van Camp, Stephanie M Fischer, Jessica L. Sorensen, Henri A. M. Marres, Uppala Radhakrishna, Katherine O. Welch, William J. KimberlingAbstract:Branchio-Oto-Renal Syndrome (BOR) is an autosomal dominant disorder characterized by the association of branchial and external ear malformations, hearing loss, and renal anomalies. The phenotype varies from ear pits to profound hearing loss, branchial fistulae, and kidney agenesis. The most common gene mutated in BOR families is EYA1, a transcriptional activator. Over 80 different disease-causing mutations have been published (www.healthcare.uiowa.edu/labs/pendredandbor/, last accessed 20 November 2007). We analyzed the EYA1 coding region (16 exons) from 435 families (345 at the University of Iowa [UI] and 95 at Boys Town National Research Hospital [BTNRH], including five at both) and found 70 different EYA1 mutations in 89 families. Most of the mutations (56/70) were private. EYA1 mutations were found in 31% of families (76/248) fitting established clinical criteria for BOR and 7% of families with questionable BOR phenotype (13/187). Severity of the phenotype did not correlate with type of mutation nor with the domain involved. These results add considerably to the spectrum of EYA1 mutations associated with BOR and indicate that the BOR phenotype is an indication for molecular studies to diagnose EYA1-associated BOR.
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SIX1 Mutation Screening in 247 Branchio-Oto-Renal Syndrome Families: A Recurrent Missense Mutation
2008Co-Authors: Amit Kochhar, Richard J.h. Smith, Cor W. R. J. Cremers, William J. Kimberling, Stephanie M Fischer, Dana J. Orten, Jessica L. Sorensen, Doris DukeAbstract:Branchio-Oto-Renal Syndrome (BOR; MIM# 113650) is a clinically heterogeneous autosomal dominant form of syndromic hearing loss characterized by variable hearing impairment, malformations of the pinnae, the presence of branchial arch remnants, and various renal abnormalities. BOR Syndrome is one of the more common autosomal dominant forms of syndromic hearing impairment. It has an estimated incidence of 1:40,000 and affects 2% of profoundly deaf children (Fraser et al., 1980). Hearing loss is present in greater than 70% of affected individuals
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Evidence of progression and fluctuation of hearing impairment in Branchio-Oto-Renal Syndrome.
International Journal of Audiology, 2004Co-Authors: Martijn H. Kemperman, Shrawan Kumar, Patrick L. M. Huygen, Frank B.m. Joosten, Sacha M. P. Koch, Cor W. R. J. CremersAbstract:We retrospectively analysed long-term serial audiometry data from patients with Branchio-Oto-Renal (BOR) Syndrome to show the features of progression and fluctuation in hearing impairment and relate the findings to age and magnetic resonance imaging (MRI) findings in the petrosal bones. Thirty-two clinically affected BOR patients from six Dutch families (A–F) were included. Audiograms were available in 24 cases, covering followup intervals of between 3 and 30 years, and suitable for individual statistical analysis in 16 cases; 14 cases also had MRI findings. Significant progression in hearing impairment was found in 10 cases, while findings of significant fluctuation were made in seven cases. These findings did not clearly correlate with MRI findings. Substantial fluctuation occurred only in cases followed at a relatively young age. Patients with an enlarged endolymphatic duct and/or sac showed significantly higher sensorineural hearing thresholds than those with either normal MRI findings or cochlear/lab...
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Inner ear anomalies are frequent but nonobligatory features of the Branchio-Oto-Renal Syndrome.
Archives of Otolaryngology-head & Neck Surgery, 2002Co-Authors: Martijn H. Kemperman, Shrawan Kumar, Patrick L. M. Huygen, Frank B.m. Joosten, Sacha M. P. Koch, Cor W. R. J. CremersAbstract:Objective: To summarize the syndromic features and evaluate the presence of inner ear anomalies in 35 patients with Branchio-Oto-Renal (BOR) Syndrome from 6 families. Design: Retrospective evaluation of magnetic resonance imaging of the temporal bones and clinical features in patients with BOR Syndrome. Setting: Tertiary referral center. Patients: The study population comprised 35 clinically affected patients with BOR Syndrome from 6 families. Most of these families were followed for over 25 years. Main Outcome Measures: Twenty-four patients underwent high-resolution, heavily T2-weighted 3-dimensional magnetic resonance imaging of the temporal bones for evaluation of inner ear anomalies. Special attention was paid to the endolymphatic duct and sac. Results: A total of 7 enlarged endolymphatic ducts and sacs (3 bilaterally and 4 unilaterally) and 5 enlarged endolymphatic ducts only (2 bilaterally and 3 unilaterally) were observed. Eight hypoplastic cochleas and 6 hypoplastic labyrinths were seen bilaterally. Seven family members had normal inner ears. Conclusion: These findings suggest that inner ear anomalies are frequent but nonobligatory features of BOR Syndrome.
Dana J. Orten - One of the best experts on this subject based on the ideXlab platform.
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six1 mutation screening in 247 branchio oto renal Syndrome families a recurrent missense mutation associated with bor
Human Mutation, 2008Co-Authors: Amit Kochhar, Cor W. R. J. Cremers, William J. Kimberling, Stephanie M Fischer, Dana J. Orten, Jessica L. Sorensen, Richard J.h. SmithAbstract:Branchio-Oto-Renal Syndrome (BOR) is a clinically heterogeneous autosomal dominant form of syndromic hearing loss characterized by variable hearing impairment, malformations of the pinnae, the presence of branchial arch remnants, and various renal abnormalities. Both EYA1 and SIX1 are expressed in developing otic, branchial and renal tissue. Consistent with this expression pattern, mutations in both genes cause BOR Syndrome. Mutations in EYA1 are found in approximately 40% of patients with the BOR phenotype, however, the role of SIX1 is much lower. To date only three different SIX1 mutations have been described in BOR patients. The current screen of 247 BOR families detected five novel SIX1 mutations (c.50T>A, c.218A>C, c.317T>G, c.329G>A, c.334C>T) and one previously reported mutation (c.328C>T) seen in 5 unrelated families. All mutations are within the protein-binding Six domain. Phenotypic variability was high in these BOR families. Seven of the eight known SIX1 mutations are missense and the one in frame deletion is predicted to be functionally similar. The wide phenotypic variability precludes making genotype-phenotype correlations at this time.
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Branchio-Oto-Renal Syndrome (BOR): novel mutations in the EYA1 gene, and a review of the mutational genetics of BOR.
Human Mutation, 2008Co-Authors: Dana J. Orten, Richard J.h. Smith, Cor W. R. J. Cremers, Guy Van Camp, Stephanie M Fischer, Jessica L. Sorensen, Henri A. M. Marres, Uppala Radhakrishna, Katherine O. Welch, William J. KimberlingAbstract:Branchio-Oto-Renal Syndrome (BOR) is an autosomal dominant disorder characterized by the association of branchial and external ear malformations, hearing loss, and renal anomalies. The phenotype varies from ear pits to profound hearing loss, branchial fistulae, and kidney agenesis. The most common gene mutated in BOR families is EYA1, a transcriptional activator. Over 80 different disease-causing mutations have been published (www.healthcare.uiowa.edu/labs/pendredandbor/, last accessed 20 November 2007). We analyzed the EYA1 coding region (16 exons) from 435 families (345 at the University of Iowa [UI] and 95 at Boys Town National Research Hospital [BTNRH], including five at both) and found 70 different EYA1 mutations in 89 families. Most of the mutations (56/70) were private. EYA1 mutations were found in 31% of families (76/248) fitting established clinical criteria for BOR and 7% of families with questionable BOR phenotype (13/187). Severity of the phenotype did not correlate with type of mutation nor with the domain involved. These results add considerably to the spectrum of EYA1 mutations associated with BOR and indicate that the BOR phenotype is an indication for molecular studies to diagnose EYA1-associated BOR.
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SIX1 Mutation Screening in 247 Branchio-Oto-Renal Syndrome Families: A Recurrent Missense Mutation
2008Co-Authors: Amit Kochhar, Richard J.h. Smith, Cor W. R. J. Cremers, William J. Kimberling, Stephanie M Fischer, Dana J. Orten, Jessica L. Sorensen, Doris DukeAbstract:Branchio-Oto-Renal Syndrome (BOR; MIM# 113650) is a clinically heterogeneous autosomal dominant form of syndromic hearing loss characterized by variable hearing impairment, malformations of the pinnae, the presence of branchial arch remnants, and various renal abnormalities. BOR Syndrome is one of the more common autosomal dominant forms of syndromic hearing impairment. It has an estimated incidence of 1:40,000 and affects 2% of profoundly deaf children (Fraser et al., 1980). Hearing loss is present in greater than 70% of affected individuals
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Transcription Factor SIX5 Is Mutated in Patients with Branchio-Oto-Renal Syndrome
The American Journal of Human Genetics, 2007Co-Authors: Bethan E. Hoskins, Derek Silvius, Richard M. Raymond, Richard J.h. Smith, William J. Kimberling, Dana J. Orten, Carl H. Cramer, Dan Zou, Dominique Weil, Christine PetitAbstract:Branchio-Oto-Renal Syndrome (BOR) is an autosomal dominant developmental disorder characterized by the association of branchial arch defects, hearing loss, and renal anomalies. Mutations in EYA1 are known to cause BOR. More recently, mutations in SIX1, which interacts with EYA1, were identified as an additional cause of BOR. A second member of the SIX family of proteins, unc-39 (SIX5), has also been reported to directly interact with eya-1 in Caenorhabditis elegans. We hypothesized that this interaction would be conserved in humans and that interactors of EYA1 represent good candidate genes for BOR. We therefore screened a cohort of 95 patients with BOR for mutations in SIX5. Four different heterozygous missense mutations were identified in five individuals. Functional analyses of these mutations demonstrated that two mutations affect EYA1-SIX5 binding and the ability of SIX5 or the EYA1-SIX5 complex to activate gene transcription. We thereby identified heterozygous mutations in SIX5 as a novel cause of BOR.
Shrawan Kumar - One of the best experts on this subject based on the ideXlab platform.
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SIX1 mutations cause Branchio-Oto-Renal Syndrome by disruption of EYA1-SIX1-DNA complexes.
Proceedings of the National Academy of Sciences, 2004Co-Authors: Rainer G. Ruf, Derek Silvius, Edgar A. Otto, Frank Beekmann, Ulla Muerb, Shrawan Kumar, Thomas J. Neuhaus, Markus J. Kemper, Richard M. RaymondAbstract: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.
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Evidence of progression and fluctuation of hearing impairment in Branchio-Oto-Renal Syndrome.
International Journal of Audiology, 2004Co-Authors: Martijn H. Kemperman, Shrawan Kumar, Patrick L. M. Huygen, Frank B.m. Joosten, Sacha M. P. Koch, Cor W. R. J. CremersAbstract:We retrospectively analysed long-term serial audiometry data from patients with Branchio-Oto-Renal (BOR) Syndrome to show the features of progression and fluctuation in hearing impairment and relate the findings to age and magnetic resonance imaging (MRI) findings in the petrosal bones. Thirty-two clinically affected BOR patients from six Dutch families (A–F) were included. Audiograms were available in 24 cases, covering followup intervals of between 3 and 30 years, and suitable for individual statistical analysis in 16 cases; 14 cases also had MRI findings. Significant progression in hearing impairment was found in 10 cases, while findings of significant fluctuation were made in seven cases. These findings did not clearly correlate with MRI findings. Substantial fluctuation occurred only in cases followed at a relatively young age. Patients with an enlarged endolymphatic duct and/or sac showed significantly higher sensorineural hearing thresholds than those with either normal MRI findings or cochlear/lab...
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Inner ear anomalies are frequent but nonobligatory features of the Branchio-Oto-Renal Syndrome.
Archives of Otolaryngology-head & Neck Surgery, 2002Co-Authors: Martijn H. Kemperman, Shrawan Kumar, Patrick L. M. Huygen, Frank B.m. Joosten, Sacha M. P. Koch, Cor W. R. J. CremersAbstract:Objective: To summarize the syndromic features and evaluate the presence of inner ear anomalies in 35 patients with Branchio-Oto-Renal (BOR) Syndrome from 6 families. Design: Retrospective evaluation of magnetic resonance imaging of the temporal bones and clinical features in patients with BOR Syndrome. Setting: Tertiary referral center. Patients: The study population comprised 35 clinically affected patients with BOR Syndrome from 6 families. Most of these families were followed for over 25 years. Main Outcome Measures: Twenty-four patients underwent high-resolution, heavily T2-weighted 3-dimensional magnetic resonance imaging of the temporal bones for evaluation of inner ear anomalies. Special attention was paid to the endolymphatic duct and sac. Results: A total of 7 enlarged endolymphatic ducts and sacs (3 bilaterally and 4 unilaterally) and 5 enlarged endolymphatic ducts only (2 bilaterally and 3 unilaterally) were observed. Eight hypoplastic cochleas and 6 hypoplastic labyrinths were seen bilaterally. Seven family members had normal inner ears. Conclusion: These findings suggest that inner ear anomalies are frequent but nonobligatory features of BOR Syndrome.
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The Branchio-Oto-Renal Syndrome.
Advances in Oto-Rhino-Laryngology, 2002Co-Authors: Martijn H. Kemperman, Shrawan Kumar, C.i.c. Stinckens, Frank B.m. Joosten, P.l.m. Huygen, C.w.r.j. CremersAbstract:Publisher Summary This chapter presents information on the diagnosis, genetics, and most characteristic symptoms of Branchio-Oto-Renal (BOR) Syndrome. The BOR Syndrome is a Mendelian developmental disorder with branchial, otic, and renal manifestations. Hearing loss is the major feature of BOR Syndrome and occurs in 93% of patients. The age of onset varies from early childhood to young adulthood. The impairment can be conductive, sensorineural, or mixed. Branchial cysts or fistulas are seen in approximately 65% of patients. These hallmark features may be either uni- or bilateral and are usually located on the external lower third of the neck, anterior to the sternocleidomastoid muscle. The clinical diagnosis of BOR Syndrome is based on the presence of two or more of the findings such as pre-auricular pits, pinnae deformities, branchial fistulas, hearing loss, and renal anomalies. Genetic testing can confirm a clinical diagnosis of BOR Syndrome and provide genetic recurrence risk information to families. There are at least 61 different mutations in the EYA1 gene identified in BOR Syndrome patients. The mutations include large and small deletions and nonsense, missense, frameshift, aberrant splicing and exon skipping mutations. Mutations in the EYA1 gene are detected in patients with branchial and otic anomalies, but without the renal anomalies (BO Syndrome), thus demonstrating that BOR and BO Syndromes are allelic. The clinical signs of BOR Syndrome are indicative of an early developmental defect of the branchial arch apparatus, the otic vesicle and/or surrounding periotic mesenchyme and the mesonephros/metanephros, taking place between the 4th and 10th weeks of human embryonic development. It is therefore very likely that EYA1 and SIX1 have critical roles in the development of these tissues.
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progressive fluctuant hearing loss enlarged vestibular aqueduct and cochlear hypoplasia in branchio oto renal Syndrome
Otology & Neurotology, 2001Co-Authors: Martijn H. Kemperman, Shrawan Kumar, C.i.c. Stinckens, P.l.m. Huygen, F B M Joosten, C.w.r.j. CremersAbstract:OBJECTIVE: To study the results of petrosal bone imaging and audiometric long-term follow-up of two patients with Branchio-Oto-Renal (BOR) Syndrome and relate them to the clinical features, including caloric responses. STUDY DESIGN: Longitudinal case study. SETTING: Tertiary referral center. PATIENTS: A father and son with the BOR Syndrome. MAIN OUTCOME MEASURES: Both patients underwent imaging studies to detect and evaluate inner ear anomalies. Longitudinal audiometric analysis of the hearing threshold data over the previous 23 years was performed. Caloric tests were performed at various ages. RESULTS: The son had a short, wide internal acoustic canal, a hypoplastic cochlea, a plump vestibule, and a wide vestibular aqueduct on both sides; the semicircular canals and endolymphatic sac were of normal size. He showed progressive fluctuant sensorineural hearing loss. Caloric tests disclosed hyporeflexia on the left side. The father had a plump internal acoustic canal and hypoplastic cochlea on both sides. The left vestibule was hypoplastic, and the left vestibular aqueduct was marginally enlarged. He showed severe hearing impairment, without substantial progression or fluctuation, and caloric areflexia on the left side. CONCLUSION: These findings suggest a correlation between progressive fluctuant sensorineural hearing loss with caloric hypofunction and the presence of an enlarged vestibular aqueduct in the BOR Syndrome. Additional longitudinal case studies are needed to further evaluate such a correlation.