Inner ear and kidney anomalies caused by IAP insertion in an intron of the Eya1 gene in a mouse model of BOR syndrome.
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A spontaneous mutation causing deafness and circling behavior was discovered in a C3H/HeJ colony of mice at the Jackson Laboratory. Pathological analysis of mutant mice revealed gross morphological abnormalities of the inner ear, and also dysmorphic or missing kidneys. The deafness and abnormal behavior were shown to be inherited as an autosomal recessive trait and mapped to mouse chromosome 1 near the position of the Eya1 gene. The human homolog of this gene, EYA1, has been shown to underly branchio-oto-renal (BOR) syndrome, an autosomal dominant disorder characterized by hearing loss with associated branchial and renal anomalies. Molecular analysis of the Eya1 gene in mutant mice revealed the insertion of an intracisternal A particle (IAP) element in intron 7. The presence of the IAP insertion was associated with reduced expression of the normal Eya1 message and formation of additional aberrant transcripts. The hypomorphic nature of the mutation may explain its recessive inheritance, if protein levels in homozygotes, but not heterozygotes, are below a critical threshold needed for normal developmental function. The new mouse mutation is designated Eya1(bor) to denote its similarity to human BOR syndrome, and will provide a valuable model for studying mutant gene expression and etiology. (+info)
Human NDUFB9 gene: genomic organization and a possible candidate gene associated with deafness disorder mapped to chromosome 8q13.
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Human NADH dehydrogenase (ubiquinone) 1beta-subcomplex, 9 (NDUFB9) is a nuclear encoded mitochondrial protein with the respiratory electron transport chain. It has been physically mapped to a 1-Mb deletion at chromosome 8q13 which also contains the gene for branchio-oto-renal (BOR) syndrome. BOR syndrome is characterized by branchial and renal abnormalities with hearing impairment. Since several hereditary deafness disorders have been associated with mitochondrial mutations, NDUFB9 was considered a candidate gene for BOR syndrome. Recently, EYA1 gene has been identified in the region which underlies the BOR syndrome but majority of BOR families did not show mutations in the EYA1 gene. Here we have determined the genomic structure of the NDUFB9 gene, including the nucleotide sequence, organization and the boundaries of the four coding exons. PCR primers were designed from the adjacent intron sequences that allow amplification of the four exons that encode the complete open reading frame. To identify whether mutations in NDUFB9 are involved in causing the BOR syndrome, we screened 9 BOR families which did not show mutations in the EYA1 gene by heteroduplex analysis; however, no mutations were found. (+info)
Mutations of a human homologue of the Drosophila eyes absent gene (EYA1) detected in patients with congenital cataracts and ocular anterior segment anomalies.
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The Drosophila eyes absent gene ( eya ) is involved in the formation of compound eyes. Flies with loss-of-function mutations of this gene develop no eyes and form the ectopic eye in the antennae and the ventral zone of the head on target expression. A highly conserved homo-logous gene in various invertebrates and vertebrates has been shown to function in the formation of the eye. In contrast, a human homologue, EYA1, has been identified by positional cloning as a candidate gene for branchio-oto-renal (BOR) syndrome, in which phenotypic manifestations are restricted to the areas of branchial arch, ear and kidney, with usually no anomalies in the eye. We have examined genomic DNA isolated from patients with various types of developmental eye anomaly for EYA1 mutations by the use of polymerase chain reaction-single-strand conformation polymorphism and sequencing. We identified three novel missense mutations in patients who had con-genital cataracts and ocular anterior segment anomalies. One of the patients had clinical features of BOR syndrome as well. This result implies that the human EYA1 gene is also involved in eye morphogenesis, and that a wide variety of clinical manifestations may be caused by EYA1 mutations. (+info)
Genomewide search and genetic localization of a second gene associated with autosomal dominant branchio-oto-renal syndrome: clinical and genetic implications.
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Branchio-oto-renal (BOR) syndrome is characterized by ear malformations, cervical fistulas, hearing loss, and renal anomalies. It is an autosomal dominant disorder with variable clinical manifestations. The most common features of BOR syndrome are branchial, hearing, and renal anomalies. However, many affected subjects have been observed with branchial-cleft anomalies and hearing loss but without renal anomalies, a condition called "branchio-otic" (BO) syndrome. It is logical to question whether the BOR and BO syndromes are allelic or whether they represent distinct genetic entities. We identified a very large extended family whose members had branchial and hearing anomalies associated with commissural lip pits that segregated in an autosomal dominant fashion. Using a genomewide search strategy, we identified genetic linkage, with a maximum LOD score of 4.81 at recombination fraction 0, between the BO phenotype and polymorphic marker D1S2757 in the genetic region of chromosome 1q31. This is the first report of linkage for a second gene associated with BOR syndrome. The findings have important clinical implications and will provide insight into the genetic basis of BOR syndrome. (+info)
Multiple intracranial aneurysms associated with branchio-oto-dysplasia.
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Branchio-oto-dysplasia is characterized by abnormalities of embryonic branchial arch system and deafness inherited as autosomal dominant with variable gene expression. We present a rare case of multiple intracranial aneurysms associated with branchio-oto-dysplasia. A 40-yr-old man with severe headache presented as spontaneous subarachnoid hemorrhage on brain computed tomographic scan. The patient also manifested clinical features of branchio-oto-dysplasia and right hemifacial hypoplasia. Carotid angiogram confirmed an aneurysm in the anterior communicating artery. Intraoperative findings demonstrated multiple aneurysms in the anterior communicating artery and in the left posterior communicating artery, which were clipped successfully. Postoperative course was uneventful. This condition has not been reported previously. We also reviewed literatures to discuss whether the intracranial aneurysm was as a coincidental finding or a part of this malformation. (+info)
Molecular effects of Eya1 domain mutations causing organ defects in BOR syndrome.
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Eya1 is a critical gene for mammalian organogenesis. Mutations in human EYA1 cause branchio-oto-renal (BOR) syndrome, an autosomal dominant disorder characterized by varying combinations of branchial, otic and renal anomalies, whereas deletion of mouse Eya1 results in the absence of multiple organ formation. Eya1 and other Eya gene products share a highly conserved 271 amino acid Eya domain that is required for protein-protein interaction. Recently, several point mutations that result in single amino acid substitutions in the conserved Eya domain region of EYA1 have been identified in BOR patients; however, the molecular and developmental basis of organ defects that occurred in BOR syndrome is unclear. To understand how these point mutations cause disease, we have analyzed the functional importance of these Eya domain missense mutations with respect to protein complex formation and cellular localization. We have demonstrated that these point mutations do not alter protein localization. However, four mutations are crucial for protein-protein interactions in both yeast and mammalian cells. Our results provide insights into the molecular mechanisms of organ defects detected in human syndromes. (+info)
A family with the branchio-oto-renal syndrome: clinical and genetic correlations.
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BACKGROUND: The branchio-oto-renal (BOR) syndrome is an autosomal dominant disease characterized by hearing loss of early onset, preauricular pits, branchial clefts, and early progressive chronic renal failure in up to 40% of family affected members. So far, it has not received due attention in the adult European nephrology literature and because of the combination of deafness with chronic renal failure it may be confused with the Alport syndrome. The BOR syndrome is caused by mutations in the EYA1 gene that maps on chromosome 8q13.3. METHODS: A three-generation, 20-member large BOR Greek-Cypriot family has been studied and followed up clinically over a 27-year period. The findings in four individuals who developed early onset renal failure are described in detail. Genetic DNA linkage studies have also been carried out. RESULTS: Of the 15 family members at risk, 14 were tested with DNA linkage analysis. Ten members were genetically affected and four were normal. All 10 affected members developed early-onset deafness. Some had different ear lobe abnormalities. Nine affected members had preauricular pits. In some of the patients these pits were deep and prominent while in others they were minor and superficial. Eight affected members had early-onset branchial clefts that needed early corrective surgery without the correct familial diagnosis ever being made. End-stage renal disease (ESRD) developed in four members at ages 36, 14, 17, and 17 with minimal proteinuria, if any. This was due to unilateral renal agenesis with contralateral hypodysplasia or bilateral, severe renal hypodysplasia. CONCLUSION: The BOR syndrome is an infrequent but well-described entity that combines early-onset renal failure and deafness together with branchial clefts and preauricular pits. Renal agenesis and dysplasia are the causes of ESRD in these individuals. Other renal abnormalities include bifid kidneys with double ureters, vesico-ureteric reflux and pelvi-ureteric stenoses. The BOR syndrome should be included in the differential diagnosis of deafness and chronic renal failure in childhood and adolescence. (+info)
Genomic rearrangements of EYA1 account for a large fraction of families with BOR syndrome.
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Branchio-Oto-Renal (BOR) syndrome is transmitted as an autosomal dominant disorder, affects an estimated 2% of profoundly deaf children, and is caused by mutations in the human EYA1 gene. However, in up to half of the reported cases, EYA1 mutation screening is negative. This finding has been taken as evidence of genetic heterogeneity. Mutation screening of the coding region of EYA1 in a panel of families linked to chromosome 8 was conducted using SSCP and direct sequencing. Only one point mutation in five probands was detected. However, complex rearrangements, such as inversions or large deletions, were discovered in the other four patients using Southern blot analysis. These data suggest that more complex rearrangements may remain undetected in EYA1 since SSCP and sequencing were commonly used to detect mutations in this gene. (+info)