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Ambroise Wonkam - One of the best experts on this subject based on the ideXlab platform.
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gjb2 and GJB6 mutations in hereditary recessive non syndromic hearing impairment in cameroon
Genes, 2019Co-Authors: Edmond Wonkam, Samuel Mawuli Adadey, Jean Jacques Noubiap, Emile R Chimusa, Jean Valentin F Fokouo, Ambroise WonkamAbstract:This study aimed to investigate GJB2 (connexin 26) and GJB6 (connexin 30) mutations associated with familial non-syndromic childhood hearing impairment (HI) in Cameroon. We selected only families segregating HI, with at least two affected individuals and with strong evidence of non-environmental causes. DNA was extracted from peripheral blood, and the entire coding region of GJB2 was interrogated using Sanger sequencing. Multiplex PCR and Sanger sequencing were used to analyze the prevalence of the GJB6-D3S1830 deletion. A total of 93 patients, belonging to 41 families, were included in the analysis. Hearing impairment was sensorineural in 51 out of 54 (94.4%) patients. Pedigree analysis suggested autosomal recessive inheritance in 85.4% (35/41) of families. Hearing impairment was inherited in an autosomal dominant and mitochondrial mode in 12.2% (5/41) and 2.4% (1/41) of families, respectively. Most HI participants were non-syndromic (92.5%; 86/93). Four patients from two families presented with type 2 Waardenburg syndrome, and three cases of type 2 Usher syndrome were identified in one family. No GJB2 mutations were found in any of the 29 families with non-syndromic HI. Additionally, the GJB6-D3S1830 deletion was not identified in any of the HI patients. This study confirms that mutations in the GJB2 gene and the del(GJB6-D13S1830) mutation do not contribute to familial HI in Cameroon.
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GJB2 and GJB6 Mutations in Non-Syndromic Childhood Hearing Impairment in Ghana.
Frontiers in Genetics, 2019Co-Authors: Samuel Mawuli Adadey, Noluthando Manyisa, Khuthala Mnika, Victoria Nembaware, Gordon A. Awandare, Osbourne Quaye, Carmen De Kock, Geoggrey Kwabla Amedofu, Ambroise WonkamAbstract:Our study aimed to investigate GJB2 (connexin 26) and GJB6 (connexin 30) mutations associated with non-syndromic childhood hearing impairment (HI) as well as the environmental causes of HI in Ghana. Medical reports of 1104 students attending schools for the deaf were analyzed. Families segregating HI, as well as isolated cases of HI of putative genetic origin were recruited. DNA was extracted from peripheral blood followed by Sanger sequencing of the entire coding region of GJB2. Multiplex PCR and Sanger sequencing were used to analyze the prevalence of GJB6-D3S1830 deletion. Ninety-seven (97) families segregating HI were identified, with 235 affected individuals; and a total of 166 isolated cases of putative genetic causes, were sampled from 11 schools for the deaf in Ghana. The environmental factors, particularly meningitis, remain a major cause of HI impairment in Ghana. The male/female ratio was 1.49. Only 59.6% of the patients had their first comprehensive HI test between 6 to 11 years of age. Nearly all the participants had sensorineural HI (99.5%; n = 639). The majority had pre-lingual HI (68.3%, n = 754), of which 92.8% were congenital. Pedigree analysis suggested autosomal recessive inheritance in 96.9% of the familial cases. GJB2-R143W mutation, previously reported as founder a mutation in Ghana accounted for 25.9% (21/81) in the homozygous state in familial cases, and in 7.9% (11/140) of non-familial non-syndromic congenital HI cases, of putative genetic origin. In a control population without HI, we found a prevalent of GJB2-R143W carriers of 1.4% (2/145), in the heterozygous state. No GJB6-D3S1830 deletion was identified in any of the HI patients. GJB2-R143W mutation accounted for over a quarter of familial non-syndromic HI in Ghana and should be investigated in clinical practice. The large connexin 30 gene deletion (GJB6-D3S1830 deletion) does not account for of congenital non-syndromic HI in Ghana. There is a need to employ Next Generation Sequencing approaches and functional genomics studies to identify the other genes involved in most families and isolated cases of HI in Ghana.
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no evidence for clinical utility in investigating the connexin genes gjb2 GJB6 and gja1 in non syndromic hearing loss in black africans
South African Medical Journal, 2014Co-Authors: Ambroise Wonkam, Jason Bosch, Kamogelo Lebeko, Nomlindo Makubalo, Jean Jacques Noubiap, Collet DandaraAbstract:Background. Deafness is the most common sensory disability in the world. Globally, mutations in GJB2 (connexin 26) have been shown to play a major role in non-syndromic deafness. Two other connexin genes, GJB6 (connexin 30) and GJA1 (connexin 43), have been implicated in hearing loss, but these genes have seldom been investigated in black Africans. We aimed to validate the utility of testing for GJB2 , GJB6 and GJA1 in an African context. Methods. Two hundred and five patients with non-syndromic deafness from Cameroon and South Africa had the full coding regions of GJB2 sequenced. Subsequently, a carefully selected subset of 100 patients was further sequenced for GJB6 and GJA1 using Sanger cycle sequencing. In addition, the large-scale GJB6 -D3S1830 deletion was investigated. Results. No pathogenic mutations that could explain the hearing loss were detected in GJB2 , GJB6 or GJA1 , and the GJB6 -D3S1830 deletion was not detected. There were no statistically significant differences in genomic variations in these genes between patients and controls. A comprehensive literature review supported these findings. Conclusion. Mutations in GJB2, GJB6 and GJA1 are not a major cause of non-syndromic deafness in black Africans and should not be investigated routinely in clinical practice.
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in search of genetic markers for nonsyndromic deafness in africa a study in cameroonians and black south africans with the GJB6 and gja1 candidate genes
Omics A Journal of Integrative Biology, 2014Co-Authors: Jason Bosch, Kamogelo Lebeko, Jean Jacques Noubiap Nziale, Nomlindo Makubalo, Collet Dandara, Ambroise WonkamAbstract:Abstract Deafness is the most common sensory disability in the world and has a variety of causes. Globally, mutations in GJB2 have been shown to play a major role in nonsyndromic deafness, but this has not been seen in Africans. Two other connexin genes, GJB6 and GJA1, have been implicated in hearing loss but have seldom been investigated in African populations. We set out to investigate the role of genetic variation in GJB6 and GJA1 in a group of Cameroonian and South African Blacks with nonsyndromic recessive hearing loss. A subset of 100 patients, affected with nonsyndromic hearing loss, from a cohort that was previously shown not to have GJB2 mutation, was analyzed by Sanger sequencing of the entire coding regions of GJB6 and GJA1. In addition, the large-scale GJB6-D3S1830 deletion was also investigated. No pathogenic mutation was detected in either GJB6 or GJA1, nor was the GJB6-D3S1830 deletion detected. There were no statistically significant differences in sequence variants between patients and co...
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in search of genetic markers for nonsyndromic deafness in africa a study in cameroonians and black south africans with the GJB6 and gja1 candidate genes
Omics A Journal of Integrative Biology, 2014Co-Authors: Jason Bosch, Kamogelo Lebeko, Jean Jacques Noubiap Nziale, Nomlindo Makubalo, Collet Dandara, Ambroise WonkamAbstract:Deafness is the most common sensory disability in the world and has a variety of causes. Globally, mutations in GJB2 have been shown to play a major role in nonsyndromic deafness, but this has not been seen in Africans. Two other connexin genes, GJB6 and GJA1, have been implicated in hearing loss but have seldom been investigated in African populations. We set out to investigate the role of genetic variation in GJB6 and GJA1 in a group of Cameroonian and South African Blacks with nonsyndromic recessive hearing loss. A subset of 100 patients, affected with nonsyndromic hearing loss, from a cohort that was previously shown not to have GJB2 mutation, was analyzed by Sanger sequencing of the entire coding regions of GJB6 and GJA1. In addition, the large-scale GJB6-D3S1830 deletion was also investigated. No pathogenic mutation was detected in either GJB6 or GJA1, nor was the GJB6-D3S1830 deletion detected. There were no statistically significant differences in sequence variants between patients and controls. Mutations in GJB6 and GJA1 are not a major cause of nonsyndromic deafness in this group of Africans from Cameroon and South Africa. Currently, there is no sufficient evidence to support their testing in a clinical setting for individuals of African ancestry.
Iris Schrijver - One of the best experts on this subject based on the ideXlab platform.
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Allele-specific impairment of GJB2 expression by GJB6 deletion del(GJB6-D13S1854).
PloS one, 2011Co-Authors: Juan Rodriguez-paris, Marta L. Tamayo, Nancy Gelvez, Iris SchrijverAbstract:Mutations in the GJB2 gene, which encodes connexin 26, are a frequent cause of congenital non-syndromic sensorineural hearing loss. Two large deletions, del(GJB6-D13S1830) and del(GJB6-D13S1854), which truncate GJB6 (connexin 30), cause hearing loss in individuals homozygous, or compound heterozygous for these deletions or one such deletion and a mutation in GJB2. Recently, we have demonstrated that the del(GJB6-D13S1830) deletion contributes to hearing loss due to an allele-specific lack of GJB2 mRNA expression and not as a result of digenic inheritance, as was postulated earlier. In the current study we investigated the smaller del(GJB6-D13S1854) deletion, which disrupts the expression of GJB2 at the transcriptional level in a manner similar to the more common del(GJB6-D13S1830) deletion. Interestingly, in the presence of this deletion, GJB2 expression remains minimally but reproducibly present. The relative allele-specific expression of GJB2 was assessed by reverse-transcriptase PCR and restriction digestions in three probands who were compound heterozygous for a GJB2 mutation and del(GJB6-D13S1854). Each individual carried a different sequence variant in GJB2. All three individuals expressed the mutated GJB2 allele in trans with del(GJB6-D13S1854), but expression of the GJB2 allele in cis with the deletion was almost absent. Our study clearly corroborates the hypothesis that the del(GJB6-D13S1854), similar to the larger and more common del(GJB6-D13S1830), removes (a) putative cis-regulatory element(s) upstream of GJB6 and narrows down the region of location.
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The digenic hypothesis unraveled: the GJB6 del(GJB6-D13S1830) mutation causes allele-specific loss of GJB2 expression in cis.
Biochemical and Biophysical Research Communications, 2009Co-Authors: Juan Rodriguez-paris, Iris SchrijverAbstract:Abstract Connexin 26 and connexin 30 are the major connexins expressed in the cochlea, where they are co-localized and form heteromeric gap junctions. Mutations in the GJB2 gene, which encodes connexin 26, are the most common cause of prelingual non-syndromic sensorineural hearing loss. The large del( GJB6 -D13S1830) mutation which involves GJB6 (connexin 30), causes hearing loss in homozygous individuals, or when compound heterozygous with a GJB2 mutation. Until now, it remained unresolved whether this phenomenon results from digenic inheritance or because of lack of GJB2 mRNA expression. After RNA extraction from buccal epithelium, a tissue known to express connexin 26 as well as connexin 30, allele-specific expression of GJB2 was investigated by reverse-transcriptase PCR and restriction digestions in three unrelated individuals compound heterozygous for a GJB2 mutation and del( GJB6 -D13S1830). Each proband carried a different sequence change in GJB2 . The mutated GJB2 allele in trans with del( GJB6 -D13S1830) was expressed in all three individuals whereas the GJB2 allele located in c is with the deletion was not expressed at all. Thus, mutations in these two genes do not cause hearing loss through a digenic mechanism of inheritance alone, as was postulated previously, but instead GJB2 expression is abolished through an effect in cis with the deletion. Our study provides unequivocal support for the hypothesis that del( GJB6 -D13S1830) eliminates a putative cis -regulatory element located within the deleted region.
Felipe Moreno - One of the best experts on this subject based on the ideXlab platform.
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uniparental disomy of chromosome 13q causing homozygosity for the 35delg mutation in the gene encoding connexin26 gjb2 results in prelingual hearing impairment in two unrelated spanish patients
Journal of Medical Genetics, 2003Co-Authors: Araceli Alvarez, Manuela Villamar, Miguel A Morenopelayo, I Del Castillo, Alejandra Pera, T Rivera, J Solanellas, Felipe MorenoAbstract:Inherited hearing impairment is a highly heterogeneous group of disorders with an overall incidence of about 1 in 2000 newborns.1 In approximately 70% of cases, the auditory impairment is not associated with other clinical features, that is, it is non-syndromic. The most frequent condition is a severe or profound hearing loss of prelingual onset, which is inherited mainly as an autosomal recessive trait.1 To date, 31 different DFNB loci for autosomal recessive non-syndromic hearing loss have been reported, and 16 genes have been identified.2 Among these loci, DFNB1 in 13q12 stands out because of its complexity and clinical relevance. It contains the gene GJB2 , which encodes connexin26, a component of intercellular gap junctions. Mutations in the GJB2 gene are responsible for up to 50% of all cases of autosomal recessive hearing impairment in most of the populations tested so far, with a frequent mutation (35delG) accounting for up to 86% of the GJB2 mutant alleles in white populations.3,4 However, not all the DFNB1 mutations affect the GJB2 gene. Recently, several research teams found a deletion in the 13q12 region which is frequently inherited in double heterozygosity with mutant GJB2 alleles in affected subjects,5–7 but it was also found in homozygosity.6,7 Molecular characterisation of this deletion, termed del( GJB6 -D13S1830), showed that it encompasses 342 kb and it does not affect the GJB2 gene, but it truncates the gene encoding connexin30 ( GJB6 ), another gap junction protein expressed in the inner ear.6 The existence of this deletion was first suspected by the finding of inconsistencies in the segregation of genetic markers distal to GJB2 . ### Key points
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a deletion involving the connexin 30 gene in nonsyndromic hearing impairment
The New England Journal of Medicine, 2002Co-Authors: Ignacio Del Castillo, Francisco J Del Castillo, Araceli Alvarez, Ibis Menendez, Manuela Villamar, Miguel A Morenopelayo, D. Telleria, Felipe MorenoAbstract:Background Inherited hearing impairment affects about 1 in 2000 newborns. Up to 50 percent of all patients with autosomal recessive nonsyndromic prelingual deafness in different populations have mutations in the gene encoding the gap-junction protein connexin 26 (GJB2) at locus DFNB1 on chromosome 13q12. However, a large fraction (10 to 42 percent) of patients with GJB2 mutations have only one mutant allele; the accompanying mutation has not been identified. DFNB1-linked familial cases with no mutation in GJB2 have also been reported. Methods We evaluated 33 unrelated probands with nonsyndromic prelingual deafness who had only one GJB2 mutant allele. Nine subjects had evidence of linkage to DFNB1. We used haplotype analysis for markers on 13q12 to search for mutations other than the one involving GJB2. Results We identified a 342-kb deletion in the gene encoding connexin 30 (GJB6), a protein that is reported to be expressed with connexin 26 in the inner ear. The deletion extended distally to GJB2, which r...
Miguel A Morenopelayo - One of the best experts on this subject based on the ideXlab platform.
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prevalence and evolutionary origins of the del GJB6 d13s1830 mutation in the dfnb1 locus in hearing impaired subjects a multicenter study
American Journal of Human Genetics, 2003Co-Authors: Ignacio Del Castillo, Arti Pandya, Miguel A Morenopelayo, Sandrine Marlin, Francisco J Del Castillo, Zippora Brownstein, Quint Adina, David J Cockburn, Kirby Siemering, Parker G ChamberlinAbstract:Mutations in GJB2, the gene encoding connexin-26 at the DFNB1 locus on 13q12, are found in as many as 50% of subjects with autosomal recessive, nonsyndromic prelingual hearing impairment. However, genetic diagnosis is complicated by the fact that 10%–50% of affected subjects with GJB2 mutations carry only one mutant allele. Recently, a deletion truncating the GJB6 gene (encoding connexin-30), near GJB2 on 13q12, was shown to be the accompanying mutation in ∼50% of these deaf GJB2 heterozygotes in a cohort of Spanish patients, thus becoming second only to 35delG at GJB2 as the most frequent mutation causing prelingual hearing impairment in Spain. Here, we present data from a multicenter study in nine countries that shows that the deletion is present in most of the screened populations, with higher frequencies in France, Spain, and Israel, where the percentages of unexplained GJB2 heterozygotes fell to 16.0%–20.9% after screening for the del(GJB6-D13S1830) mutation. Our results also suggest that additional mutations remain to be identified, either in DFNB1 or in other unlinked genes involved in epistatic interactions with GJB2. Analysis of haplotypes associated with the deletion revealed a founder effect in Ashkenazi Jews and also suggested a common founder for countries in Western Europe. These results have important implications for the diagnosis and counseling of families with DFNB1 deafness.
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uniparental disomy of chromosome 13q causing homozygosity for the 35delg mutation in the gene encoding connexin26 gjb2 results in prelingual hearing impairment in two unrelated spanish patients
Journal of Medical Genetics, 2003Co-Authors: Araceli Alvarez, Manuela Villamar, Miguel A Morenopelayo, I Del Castillo, Alejandra Pera, T Rivera, J Solanellas, Felipe MorenoAbstract:Inherited hearing impairment is a highly heterogeneous group of disorders with an overall incidence of about 1 in 2000 newborns.1 In approximately 70% of cases, the auditory impairment is not associated with other clinical features, that is, it is non-syndromic. The most frequent condition is a severe or profound hearing loss of prelingual onset, which is inherited mainly as an autosomal recessive trait.1 To date, 31 different DFNB loci for autosomal recessive non-syndromic hearing loss have been reported, and 16 genes have been identified.2 Among these loci, DFNB1 in 13q12 stands out because of its complexity and clinical relevance. It contains the gene GJB2 , which encodes connexin26, a component of intercellular gap junctions. Mutations in the GJB2 gene are responsible for up to 50% of all cases of autosomal recessive hearing impairment in most of the populations tested so far, with a frequent mutation (35delG) accounting for up to 86% of the GJB2 mutant alleles in white populations.3,4 However, not all the DFNB1 mutations affect the GJB2 gene. Recently, several research teams found a deletion in the 13q12 region which is frequently inherited in double heterozygosity with mutant GJB2 alleles in affected subjects,5–7 but it was also found in homozygosity.6,7 Molecular characterisation of this deletion, termed del( GJB6 -D13S1830), showed that it encompasses 342 kb and it does not affect the GJB2 gene, but it truncates the gene encoding connexin30 ( GJB6 ), another gap junction protein expressed in the inner ear.6 The existence of this deletion was first suspected by the finding of inconsistencies in the segregation of genetic markers distal to GJB2 . ### Key points
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a deletion involving the connexin 30 gene in nonsyndromic hearing impairment
The New England Journal of Medicine, 2002Co-Authors: Ignacio Del Castillo, Francisco J Del Castillo, Araceli Alvarez, Ibis Menendez, Manuela Villamar, Miguel A Morenopelayo, D. Telleria, Felipe MorenoAbstract:Background Inherited hearing impairment affects about 1 in 2000 newborns. Up to 50 percent of all patients with autosomal recessive nonsyndromic prelingual deafness in different populations have mutations in the gene encoding the gap-junction protein connexin 26 (GJB2) at locus DFNB1 on chromosome 13q12. However, a large fraction (10 to 42 percent) of patients with GJB2 mutations have only one mutant allele; the accompanying mutation has not been identified. DFNB1-linked familial cases with no mutation in GJB2 have also been reported. Methods We evaluated 33 unrelated probands with nonsyndromic prelingual deafness who had only one GJB2 mutant allele. Nine subjects had evidence of linkage to DFNB1. We used haplotype analysis for markers on 13q12 to search for mutations other than the one involving GJB2. Results We identified a 342-kb deletion in the gene encoding connexin 30 (GJB6), a protein that is reported to be expressed with connexin 26 in the inner ear. The deletion extended distally to GJB2, which r...
Juan Rodriguez-paris - One of the best experts on this subject based on the ideXlab platform.
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Allele-specific impairment of GJB2 expression by GJB6 deletion del(GJB6-D13S1854).
PloS one, 2011Co-Authors: Juan Rodriguez-paris, Marta L. Tamayo, Nancy Gelvez, Iris SchrijverAbstract:Mutations in the GJB2 gene, which encodes connexin 26, are a frequent cause of congenital non-syndromic sensorineural hearing loss. Two large deletions, del(GJB6-D13S1830) and del(GJB6-D13S1854), which truncate GJB6 (connexin 30), cause hearing loss in individuals homozygous, or compound heterozygous for these deletions or one such deletion and a mutation in GJB2. Recently, we have demonstrated that the del(GJB6-D13S1830) deletion contributes to hearing loss due to an allele-specific lack of GJB2 mRNA expression and not as a result of digenic inheritance, as was postulated earlier. In the current study we investigated the smaller del(GJB6-D13S1854) deletion, which disrupts the expression of GJB2 at the transcriptional level in a manner similar to the more common del(GJB6-D13S1830) deletion. Interestingly, in the presence of this deletion, GJB2 expression remains minimally but reproducibly present. The relative allele-specific expression of GJB2 was assessed by reverse-transcriptase PCR and restriction digestions in three probands who were compound heterozygous for a GJB2 mutation and del(GJB6-D13S1854). Each individual carried a different sequence variant in GJB2. All three individuals expressed the mutated GJB2 allele in trans with del(GJB6-D13S1854), but expression of the GJB2 allele in cis with the deletion was almost absent. Our study clearly corroborates the hypothesis that the del(GJB6-D13S1854), similar to the larger and more common del(GJB6-D13S1830), removes (a) putative cis-regulatory element(s) upstream of GJB6 and narrows down the region of location.
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The digenic hypothesis unraveled: the GJB6 del(GJB6-D13S1830) mutation causes allele-specific loss of GJB2 expression in cis.
Biochemical and Biophysical Research Communications, 2009Co-Authors: Juan Rodriguez-paris, Iris SchrijverAbstract:Abstract Connexin 26 and connexin 30 are the major connexins expressed in the cochlea, where they are co-localized and form heteromeric gap junctions. Mutations in the GJB2 gene, which encodes connexin 26, are the most common cause of prelingual non-syndromic sensorineural hearing loss. The large del( GJB6 -D13S1830) mutation which involves GJB6 (connexin 30), causes hearing loss in homozygous individuals, or when compound heterozygous with a GJB2 mutation. Until now, it remained unresolved whether this phenomenon results from digenic inheritance or because of lack of GJB2 mRNA expression. After RNA extraction from buccal epithelium, a tissue known to express connexin 26 as well as connexin 30, allele-specific expression of GJB2 was investigated by reverse-transcriptase PCR and restriction digestions in three unrelated individuals compound heterozygous for a GJB2 mutation and del( GJB6 -D13S1830). Each proband carried a different sequence change in GJB2 . The mutated GJB2 allele in trans with del( GJB6 -D13S1830) was expressed in all three individuals whereas the GJB2 allele located in c is with the deletion was not expressed at all. Thus, mutations in these two genes do not cause hearing loss through a digenic mechanism of inheritance alone, as was postulated previously, but instead GJB2 expression is abolished through an effect in cis with the deletion. Our study provides unequivocal support for the hypothesis that del( GJB6 -D13S1830) eliminates a putative cis -regulatory element located within the deleted region.