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Christine Petit - One of the best experts on this subject based on the ideXlab platform.
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molecular genetics of hearing loss
Annual Review of Genetics, 2001Co-Authors: Christine Petit, Jacqueline Levilliers, Jeanpierre HardelinAbstract:▪ Abstract Hereditary isolated hearing loss is genetically highly heterogeneous. Over 100 genes are predicted to cause this disorder in humans. Sixty loci have been reported and 24 genes underlying 28 Deafness forms have been identified. The present epistemic stage in the realm consists in a preliminary characterization of the encoded proteins and the associated defective biological processes. Since for several of the Deafness forms we still only have fuzzy notions of their pathogenesis, we here adopt a presentation of the various Deafness forms based on the site of the primary defect: hair cell defects, nonsensory cell defects, and tectorial membrane anomalies. The various Deafness forms so far studied appear as monogenic disorders. They are all rare with the exception of one, caused by mutations in the gene encoding the gap junction protein connexin26, which accounts for between one third to one half of the cases of prelingual inherited Deafness in Caucasian populations.
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clinical features of the prevalent form of childhood Deafness dfnb1 due to a connexin 26 gene defect implications for genetic counselling
The Lancet, 1999Co-Authors: Françoise Denoyelle, D Weil, Pierre Chauvin, Sandrine Marlin, Lucien Moatti, Ereanoel Garabedian, Christine PetitAbstract:Summary Background DFNB1 , the locus of an autosomal recessive form of Deafness due to mutations in the connexin-26 gene ( CX26 or GJB2 ) is one of the most frequent hereditary defects in human beings. To date, no clinical characterisation of the DFNB1 inner-ear defects has been reported, which precludes the provision of prognostic information and genetic counselling. Methods We enrolled, in a prospective study, 140 children from 104 families affected by sensorineural Deafness with various degrees of hearing loss. The children either belonged to a family affected by autosomal recessive Deafness ( DFNB family ) or represented sporadic cases. We searched for mutations in the 5′ non-coding exon and in the coding region of CX26. Audiometric and radiological features were investigated and compared in deaf children with and without CX26 mutations. Findings CX26 mutations were present in 43 (49%) of the 88 families with cases of prelingual Deafness versus none of the 16 families with postlingual forms of Deafness (p CX26 mutations were compared with the defects in 57 prelingually deaf children without CX26 mutations. DFNB1 Deafness varied from mild to profound, associated with sloping or flat audiometric curves and a radiologically normal inner ear. Hearing loss was not progressive in 11 of 16 cases tested, and variations in the severity of Deafness between siblings were common. Interpretation The characteristic audiometric and radiological features of DFNB1 should be the reference used to guide the investigation, by CX26 molecular diagnostic tests, of deaf children with a compatible phenotype. Prognostic information can now be given to families: the hearing loss in DFNB1 Deafness is non-progressive in most cases, at least up to young adulthood. An important element for genetic counselling is that the severity of hearing loss due to DFNB1 is extremely variable and cannot be predicted, even within families.
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connexin 26 gene linked to a dominant Deafness
Nature, 1998Co-Authors: Françoise Denoyelle, G Linagranade, Hassan Chaib, D Weil, Fabienne Leviacobas, Roberto Bruzzone, Henri Plauchu, Christine PetitAbstract:A high proportion of all cases of congenital Deafness is causedby mutations in a gene coding for a gap-junction protein,connexin 26. The Deafness associated with this gene, Cx26, is the autosomal recessive form, DFNB1(refs 1–3); its involvement in autosomal dominant forms of Deafness has remained controversial4. Here we show that a mutation in Cx26 underlies the dominant form of Deafness, DFNA3.
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a gene responsible for a dominant form of neurosensory non syndromic Deafness maps to the nsrd1 recessive Deafness gene interval
Human Molecular Genetics, 1994Co-Authors: Hassan Chaib, Parry Guilford, Jacqueline Levilliers, G Linagranade, Henri Plauchu, Alain Morgon, Christine PetitAbstract:The first localization of a gene responsible for autosomal, neurosensory, recessive Deafness recently assigned NSRD1 to the centromeric region of human chromosome 13. We now report on a dominant form of neurosensory Deafness found in a family of French origin. The Deafness is moderate to severe, has a prelingual onset and affects predominantly the high frequencies. The gene responsible for this form of Deafness was found by linkage analysis to map to the same region of chromosome 13 as NSRD1. A multipoint analysis gave a maximum lod score of 4.66 with a most likely location close to locus D13S175. This suggests that different mutations in NSRD1 may cause both dominant and recessive neurosensory Deafness.
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a non syndrome form of neurosensory recessive Deafness maps to the pericentromeric region of chromosome 13q
Nature Genetics, 1994Co-Authors: Parry Guilford, Saida Ben Arab, A Belkahia, Stephane Blanchard, Jacqueline Levilliers, Jean Weissenbach, Christine PetitAbstract:Non–syndromic, recessively inherited Deafness is the most predominant form of severe inherited childhood Deafness. Until now, no gene responsible for this type of Deafness has been localized, due to extreme genetic heterogeneity and limited clinical differentiation. Linkage analyses using highly polymorphic microsatellite markers were performed on two consanguineous families from Tunisia affected by this form of Deafness. The Deafness was profound, fully penetrant and prelingual. A maximum two–point lod score of 9.88 (θ = 0.001) was found with a marker detecting a 13q locus (D13S175). Linkage was also observed to the pericentromeric 13q12 loci D13S115 and D13S143. These data map this neurosensory Deafness gene to the same region of chromosome 13q as the gene for severe, childhood autosomal recessive muscular dystrophy.
Laura G. Remsen - One of the best experts on this subject based on the ideXlab platform.
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brainstem auditory evoked potential assessment of congenital Deafness in dalmatians associations with phenotypic markers
Journal of Veterinary Internal Medicine, 1992Co-Authors: George M Strain, Michael T Kearney, Ivan J Gignac, Donald Levesque, Holly J Nelson, Bruce L Tedford, Laura G. RemsenAbstract:To screen for congenital Deafness, brainstem auditory-evoked potential (BAEP) testing was performed on 1031 Dalmatians from three geographically separated areas. Phenotypic marker assessment was done to determine markers possibly associated with Deafness. Markers included sex, hair coat color, pigmentation of different areas of skin (eye rims, nose, and ears), presence of a patch, spot size and marking (density of spotting), sire and dam BAEP status, and presence of iris and retinal tapetal pigmentation. Combined data from all test sites showed 8.1 % bilateral Deafness (N = 83 dogs) and 21.60/0 unilateral Deafness (N = 223), or an overall 29.70/0 incidence of hearing disorders. Significant (P < 0.05) associations with Deafness for the data from all test sites combined were seen for patch, sire and dam BAEP, iris pigment, and retinal pigment. However, results differed for several of the significant pheno typic markers when analyses were done on the data from the individual test sites; changes from signifi cant to not significant were found. This suggested the existence of multiple populations of Deafness patterns, and reinforced the precautionary conclusion that associations of phenotypic markers with Deafness are not necessarily functionally significant. (Journal of Veterinary Internal Medicine 1992; 6:175-182)
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brainstem auditory evoked potential assessment of congenital Deafness in dalmatians associations with phenotypic markers
Journal of Veterinary Internal Medicine, 1992Co-Authors: George M Strain, Michael T Kearney, Ivan J Gignac, Donald Levesque, Holly J Nelson, Bruce L Tedford, Laura G. RemsenAbstract:To screen for congenital Deafness, brainstem auditory-evoked potential (BAEP) testing was performed on 1031 Dalmatians from three geographically separated areas. Phenotypic marker assessment was done to determine markers possibly associated with Deafness. Markers included sex, hair coat color, pigmentation of different areas of skin (eye rims, nose, and ears), presence of a patch, spot size and marking (density of spotting), sire and dam BAEP status, and presence of iris and retinal tapetal pigmentation. Combined data from all test sites showed 8.1% bilateral Deafness (N = 83 dogs) and 21.6% unilateral Deafness (N = 223), or an overall 29.7% incidence of hearing disorders. Significant (P less than 0.05) associations with Deafness for the data from all test sites combined were seen for patch, sire and dam BAEP, iris pigment, and retinal pigment. However, results differed for several of the significant phenotypic markers when analyses were done on the data from the individual test sites; changes from significant to not significant were found. This suggested the existence of multiple populations of Deafness patterns, and reinforced the precautionary conclusion that associations of phenotypic markers with Deafness are not necessarily functionally significant.
George M Strain - One of the best experts on this subject based on the ideXlab platform.
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congenital Deafness in jack russell terriers prevalence and association with phenotype
Veterinary Journal, 2012Co-Authors: B Comito, K E Knowles, George M StrainAbstract:Congenital hereditary sensorineural Deafness is the most common form of Deafness in dogs. The objectives of this study were to determine a reliable measure of the prevalence of Deafness in Jack Russell terriers, an affected breed, and associations between Deafness and phenotypic characteristics. Brainstem auditory evoked response recordings and phenotypic parameters (coat color, coat texture, sex, eye color, sire and dam hearing status) were recorded for 1009 Jack Russell terriers. The prevalence of unilateral and bilateral Deafness was 3.57% and 0.50%, respectively, lower by a factor of three to four than in earlier reports based on smaller and closely related kindreds. Significant association with Deafness was identified with white coat color and parental hearing status, but not with sex or coat type. Lack of significant sex or coat type associations and the significant association with white coat color are consistent with previous reports. In conclusion the prevalence of Deafness in Jack Russell terriers is lower than initially reported. Deafness was associated with white coat color and parental hearing status. The association with parental hearing status supports this form of Deafness being a heritable trait in the breed and the association with white coat color supports an inheritance linked to pigmentation genes.
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Deafness prevalence and pigmentation and gender associations in dog breeds at risk
Veterinary Journal, 2004Co-Authors: George M StrainAbstract:Hearing function was tested in dogs from breeds at risk for pigment-associated congenital sensorineural Deafness - Dalmatian, English setter (ES), English cocker spaniel (ECS), bull terrier (BT), Australian cattle dog (ACD), whippet, Catahoula leopard dog, and Jack Russell terrier. Deafness prevalence was highest in Dalmatians and lowest in ECS. Phenotype correlation studies were performed in breeds with >100 brainstem auditory evoked responses (BAER) tested subjects. No gender differences were observed. No differences were seen between black- and liver-spotted Dalmatians, among the ES roan colour varieties, among the ECS parti varieties, or among the ACD colour varieties. Blue eyes were positively associated and patches were negatively associated with Deafness in the Dalmatian. Blue eyes were also associated with Deafness in the ES and ECS. White BT were more likely than coloured BT to be deaf. Having one or more parent's ear deaf was positively associated with Deafness in Dalmatians, ES, and ECS.
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brainstem auditory evoked potential assessment of congenital Deafness in dalmatians associations with phenotypic markers
Journal of Veterinary Internal Medicine, 1992Co-Authors: George M Strain, Michael T Kearney, Ivan J Gignac, Donald Levesque, Holly J Nelson, Bruce L Tedford, Laura G. RemsenAbstract:To screen for congenital Deafness, brainstem auditory-evoked potential (BAEP) testing was performed on 1031 Dalmatians from three geographically separated areas. Phenotypic marker assessment was done to determine markers possibly associated with Deafness. Markers included sex, hair coat color, pigmentation of different areas of skin (eye rims, nose, and ears), presence of a patch, spot size and marking (density of spotting), sire and dam BAEP status, and presence of iris and retinal tapetal pigmentation. Combined data from all test sites showed 8.1 % bilateral Deafness (N = 83 dogs) and 21.60/0 unilateral Deafness (N = 223), or an overall 29.70/0 incidence of hearing disorders. Significant (P < 0.05) associations with Deafness for the data from all test sites combined were seen for patch, sire and dam BAEP, iris pigment, and retinal pigment. However, results differed for several of the significant pheno typic markers when analyses were done on the data from the individual test sites; changes from signifi cant to not significant were found. This suggested the existence of multiple populations of Deafness patterns, and reinforced the precautionary conclusion that associations of phenotypic markers with Deafness are not necessarily functionally significant. (Journal of Veterinary Internal Medicine 1992; 6:175-182)
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brainstem auditory evoked potential assessment of congenital Deafness in dalmatians associations with phenotypic markers
Journal of Veterinary Internal Medicine, 1992Co-Authors: George M Strain, Michael T Kearney, Ivan J Gignac, Donald Levesque, Holly J Nelson, Bruce L Tedford, Laura G. RemsenAbstract:To screen for congenital Deafness, brainstem auditory-evoked potential (BAEP) testing was performed on 1031 Dalmatians from three geographically separated areas. Phenotypic marker assessment was done to determine markers possibly associated with Deafness. Markers included sex, hair coat color, pigmentation of different areas of skin (eye rims, nose, and ears), presence of a patch, spot size and marking (density of spotting), sire and dam BAEP status, and presence of iris and retinal tapetal pigmentation. Combined data from all test sites showed 8.1% bilateral Deafness (N = 83 dogs) and 21.6% unilateral Deafness (N = 223), or an overall 29.7% incidence of hearing disorders. Significant (P less than 0.05) associations with Deafness for the data from all test sites combined were seen for patch, sire and dam BAEP, iris pigment, and retinal pigment. However, results differed for several of the significant phenotypic markers when analyses were done on the data from the individual test sites; changes from significant to not significant were found. This suggested the existence of multiple populations of Deafness patterns, and reinforced the precautionary conclusion that associations of phenotypic markers with Deafness are not necessarily functionally significant.
Karin Kirschhofer - One of the best experts on this subject based on the ideXlab platform.
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screening for monogenetic del gjb6 d13s1830 and digenic del gjb6 d13s1830 gjb2 patterns of inheritance in deaf individuals from eastern austria
Hearing Research, 2004Co-Authors: Klemens Frei, Reinhard Ramsebner, Trevor Lucas, Wolfdieter Baumgartner, Christian Schoefer, F Wachtler, Karin KirschhoferAbstract:Genetically caused congenital Deafness is a common trait affecting 1 in 2000 newborn children and is predominantly inherited in an autosomal recessive fashion. Genes such as the gap junction protein beta 2 (GJB2) encoding for Connexin (Cx26) and GJB6 (Cx30) are known to cause sensorineural Deafness. Autosomal recessive Deafness has been linked both to the monogenetic occurrence of mutated GJB2 or the GJB6 deletion del(GJB6-D13S1830) and digenic GJB2/del(GJB6-D13S1830) inheritance. Monogenetic GJB2 alterations are responsible for 25.5% of Deafness in the eastern Austrian population. An additional 9.8% are heterozygous carriers of a single GJB2 mutation which is not responsible for Deafness alone. Del(GJB6-D13S1830) and GJB2/del(GJB6-D13S1830) mutations have been shown to be the second most frequent cause of Deafness in different populations. To address the question of the relevance of mutations in GJB6 either as a monogenetic or a digenic GJB2/del(GJB6-D13S1830) cause of Deafness in this population, 76 unrelated individuals (33 families and 43 sporadic cases) were screened using PCR strategies. Similar to studies in other hard of hearing populations with similar or lower carrier frequencies of single GJB2 mutations, the presence of del(GJB6-D13S1830) was not detected in any individual within the patient group. Data therefore exclude a digenetic association of del(GJB6-D13S1830) with heterozygous GJB2 mutations as a cause of Deafness in a representative sample of the population from Eastern Austria.
Thomas W. White - One of the best experts on this subject based on the ideXlab platform.
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Connexin-26 mutations in Deafness and skin disease.
Expert Reviews in Molecular Medicine, 2009Co-Authors: Thomas W. WhiteAbstract:Gap junctions allow the exchange of ions and small molecules between adjacent cells through intercellular channels formed by connexin proteins, which can also form functional hemichannels in nonjunctional membranes. Mutations in connexin genes cause a variety of human diseases. For example, mutations in GJB2 , the gene encoding connexin-26 (Cx26), are not only a major cause of nonsyndromic Deafness, but also cause syndromic Deafness associated with skin disorders such as palmoplantar keratoderma, keratitis–ichthyosis Deafness syndrome, Vohwinkel syndrome, hystrix–ichthyosis Deafness syndrome and Bart–Pumphrey syndrome. The most common mutation in the Cx26 gene linked to nonsyndromic Deafness is 35ΔG, a frameshift mutation leading to an early stop codon. The large number of deaf individuals homozygous for 35ΔG do not develop skin disease. Similarly, there is abundant experimental evidence to suggest that other Cx26 loss-of-function mutations cause Deafness, but not skin disease. By contrast, Cx26 mutations that cause both skin diseases and Deafness are all single amino acid changes. Since nonsyndromic Deafness is predominantly a loss-of-function disorder, it follows that the syndromic mutants must show an alteration, or gain, of function to cause skin disease. Here, we summarise the functional consequences and clinical phenotypes resulting from Cx26 mutations that cause Deafness and skin disease.
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connexin 26 mutations in Deafness and skin disease
Expert Reviews in Molecular Medicine, 2009Co-Authors: Jack R Lee, Thomas W. WhiteAbstract:Gap junctions allow the exchange of ions and small molecules between adjacent cells through intercellular channels formed by connexin proteins, which can also form functional hemichannels in nonjunctional membranes. Mutations in connexin genes cause a variety of human diseases. For example, mutations in GJB2, the gene encoding connexin-26 (Cx26), are not only a major cause of nonsyndromic Deafness, but also cause syndromic Deafness associated with skin disorders such as palmoplantar keratoderma, keratitis-ichthyosis Deafness syndrome, Vohwinkel syndrome, hystrix-ichthyosis Deafness syndrome and Bart-Pumphrey syndrome. The most common mutation in the Cx26 gene linked to nonsyndromic Deafness is 35DeltaG, a frameshift mutation leading to an early stop codon. The large number of deaf individuals homozygous for 35DeltaG do not develop skin disease. Similarly, there is abundant experimental evidence to suggest that other Cx26 loss-of-function mutations cause Deafness, but not skin disease. By contrast, Cx26 mutations that cause both skin diseases and Deafness are all single amino acid changes. Since nonsyndromic Deafness is predominantly a loss-of-function disorder, it follows that the syndromic mutants must show an alteration, or gain, of function to cause skin disease. Here, we summarise the functional consequences and clinical phenotypes resulting from Cx26 mutations that cause Deafness and skin disease.