The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Veronique Pingault - One of the best experts on this subject based on the ideXlab platform.
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a novel mutation in the endothelin b receptor gene in a moroccan family with shah Waardenburg Syndrome
Molecular Syndromology, 2015Co-Authors: Yassamine Doubaj, Veronique Pingault, Siham Chafai Elalaoui, Ilham Ratbi, Mohamed Azouz, Hicham Zerhouni, F Ettayebi, Abdelaziz SefianiAbstract:Waardenburg Syndrome (WS) is a neurocristopathy disorder combining sensorineural deafness and pigmentary abnormalities. The presence of additional signs defines the 4 subtypes. WS type IV, also called Shah-Waardenburg Syndrome (SWS), is characterized by the association with congenital aganglionic megacolon (Hirschsprung disease). To date, 3 causative genes have been related to this congenital disorder. Mutations in the EDNRB and EDN3 genes are responsible for the autosomal recessive form of SWS, whereas SOX10 mutations are inherited in an autosomal dominant manner. We report here the case of a 3-month-old Morrocan girl with WS type IV, born to consanguineous parents. The patient had 3 cousins who died in infancy with the same symptoms. Molecular analysis by Sanger sequencing revealed the presence of a novel homozygous missense mutation c.1133A>G (p.Asn378Ser) in the EDNRB gene. The proband's parents as well as the parents of the deceased cousins are heterozygous carriers of this likely pathogenic mutation. This molecular diagnosis allows us to provide genetic counseling to the family and eventually propose prenatal diagnosis to prevent recurrence of the disease in subsequent pregnancies.
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spectrum of temporal bone abnormalities in patients with Waardenburg Syndrome and sox10 mutations
American Journal of Neuroradiology, 2013Co-Authors: Monique Elmalehberges, Sandrine Marlin, Clarisse Baumann, N Noelpetroff, A Sekkal, V Couloigner, Koenraad Devriendt, Meredith Wilson, G Sebag, Veronique PingaultAbstract:BACKGROUND AND PURPOSE: Waardenburg Syndrome, characterized by deafness and pigmentation abnormalities, is clinically and genetically heterogeneous, consisting of 4 distinct subtypes and involving several genes. SOX10 mutations have been found both in types 2 and 4 Waardenburg Syndrome and neurologic variants. The purpose of this study was to evaluate both the full spectrum and relative frequencies of inner ear malformations in these patients. MATERIALS AND METHODS: Fifteen patients with Waardenburg Syndrome and different SOX10 mutations were studied retrospectively. Imaging was performed between February 2000 and March 2010 for cochlear implant work-up, diagnosis of hearing loss, and/or evaluation of neurologic impairment. Eleven patients had both CT and MR imaging examinations, 3 had MR imaging only, and 1 had CT only. RESULTS: Temporal bone abnormalities were bilateral. The most frequent pattern associated agenesis or hypoplasia of ≥1 semicircular canal, an enlarged vestibule, and a cochlea with a reduced size and occasionally an abnormal shape, but with normal partition in the 13/15 cases that could be analyzed. Three patients lacked a cochlear nerve, bilaterally in 2 patients. In addition, associated abnormalities were found when adequate MR imaging sequences were available: agenesis of the olfactory bulbs (7/8), hypoplastic or absent lacrimal glands (11/14), hypoplastic parotid glands (12/14), and white matter signal anomalies (7/13). CONCLUSIONS: In the appropriate clinical context, bilateral agenesis or hypoplasia of the semicircular canals or both, associated with an enlarged vestibule and a cochlear deformity, strongly suggests a diagnosis of Waardenburg Syndrome linked to a SOX10 mutation.
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Alu-mediated deletion of SOX10 regulatory elements in Waardenburg Syndrome type 4.
European Journal of Human Genetics, 2012Co-Authors: Nadege Bondurand, Michel Goossens, Virginie Fouquet, Viviane Baral, Laure Lecerf, Natalie Loundon, Benedicte Duriez, Philippe Labrune, Veronique PingaultAbstract:Waardenburg Syndrome type 4 (WS4) is a rare neural crest disorder defined by the combination of Waardenburg Syndrome (sensorineural hearing loss and pigmentation defects) and Hirschsprung disease (intestinal aganglionosis). Three genes are known to be involved in this Syndrome, that is, EDN3 (endothelin-3), EDNRB (endothelin receptor type B), and SOX10. However, 15-35% of WS4 remains unexplained at the molecular level, suggesting that other genes could be involved and/or that mutations within known genes may have escaped previous screenings. Here, we searched for deletions within recently identified SOX10 regulatory sequences and describe the first characterization of a WS4 patient presenting with a large deletion encompassing three of these enhancers. Analysis of the breakpoint region suggests a complex rearrangement involving three Alu sequences that could be mediated by a FosTes/MMBIR replication mechanism. Taken together with recent reports, our results demonstrate that the disruption of highly conserved non-coding elements located within or at a long distance from the coding sequences of key genes can result in several neurocristopathies. This opens up new routes to the molecular dissection of neural crest disorders.
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screening of mitf and sox10 regulatory regions in Waardenburg Syndrome type 2
PLOS ONE, 2012Co-Authors: Viviane Baral, Michel Goossens, Sandrine Marlin, Asma Chaoui, Yuli Watanabe, Tania Attiebitach, Veronique PingaultAbstract:Waardenburg Syndrome (WS) is a rare auditory-pigmentary disorder that exhibits varying combinations of sensorineural hearing loss and pigmentation defects. Four subtypes are clinically defined based on the presence or absence of additional symptoms. WS type 2 (WS2) can result from mutations within the MITF or SOX10 genes; however, 70% of WS2 cases remain unexplained at the molecular level, suggesting that other genes might be involved and/or that mutations within the known genes escaped previous screenings. The recent identification of a deletion encompassing three of the SOX10 regulatory elements in a patient presenting with another WS subtype, WS4, defined by its association with Hirschsprung disease, led us to search for deletions and point mutations within the MITF and SOX10 regulatory elements in 28 yet unexplained WS2 cases. Two nucleotide variations were identified: one in close proximity to the MITF distal enhancer (MDE) and one within the U1 SOX10 enhancer. Functional analyses argued against a pathogenic effect of these variations, suggesting that mutations within regulatory elements of WS genes are not a major cause of this neurocristopathy.
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Identification and functional analysis of SOX10 missense mutations in different subtypes of Waardenburg Syndrome.
Human Mutation, 2011Co-Authors: Asma Chaoui, Veronique Pingault, Michel Goossens, Renaud Touraine, Viviane Baral, Yuli Watanabe, Nadege BondurandAbstract:Waardenburg Syndrome (WS) is a rare disorder characterized by pigmentation defects and sensorineural deafness, classified into four clinical subtypes, WS1-S4. Whereas the absence of additional features characterizes WS2, association with Hirschsprung disease defines WS4. WS is genetically heterogeneous, with six genes already identified, including SOX10. About 50 heterozygous SOX10 mutations have been described in patients presenting with WS2 or WS4, with or without myelination defects of the peripheral and central nervous system (PCWH, Peripheral demyelinating neuropathy-Central dysmyelinating leukodystrophy-Waardenburg Syndrome-Hirschsprung disease, or PCW, PCWH without HD). The majority are truncating mutations that most often remove the main functional domains of the protein. Only three missense mutations have been thus far reported. In the present study, novel SOX10 missense mutations were found in 11 patients and were examined for effects on SOX10 characteristics and functions. The mutations were associated with various phenotypes, ranging from WS2 to PCWH. All tested mutations were found to be deleterious. Some mutants presented with partial cytoplasmic redistribution, some lost their DNA-binding and/or transactivation capabilities on various tissue-specific target genes. Intriguingly, several mutants were redistributed in nuclear foci. Whether this phenomenon is a cause or a consequence of mutation-associated pathogenicity remains to be determined, but this observation could help to identify new SOX10 modes of action.
Nadege Bondurand - One of the best experts on this subject based on the ideXlab platform.
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ednrb mutations cause Waardenburg Syndrome type ii in the heterozygous state
Human Mutation, 2017Co-Authors: Nadege Bondurand, Laure Lecerf, Sarah Issa, Emmanuelle Faubert, Sylvain Poisson, Patrick Nitschke, Naima DeggoujAbstract:Waardenburg Syndrome (WS) is a genetic disorder characterized by sensorineural hearing loss and pigmentation anomalies. The clinical definition of four WS types is based on additional features due to defects in structures mostly arising from the neural crest, with type I and type II being the most frequent. While type I is tightly associated to PAX3 mutations, WS type II (WS2) remains partly enigmatic with mutations in known genes (MITF, SOX10) accounting for only 30% of the cases. We performed exome sequencing in a WS2 index case and identified a heterozygous missense variation in EDNRB. Interestingly, homozygous (and very rare heterozygous) EDNRB mutations are already described in type IV WS (i.e., in association with Hirschsprung disease [HD]) and heterozygous mutations in isolated HD. Screening of a WS2 cohort led to the identification of an overall of six heterozygous EDNRB variations. Clinical phenotypes, pedigrees and molecular segregation investigations unraveled a dominant mode of inheritance with incomplete penetrance. In parallel, cellular and functional studies showed that each of the mutations impairs the subcellular localization of the receptor or induces a defective downstream signaling pathway. Based on our results, we now estimate EDNRB mutations to be responsible for 5%-6% of WS2.
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Alu-mediated deletion of SOX10 regulatory elements in Waardenburg Syndrome type 4.
European Journal of Human Genetics, 2012Co-Authors: Nadege Bondurand, Michel Goossens, Virginie Fouquet, Viviane Baral, Laure Lecerf, Natalie Loundon, Benedicte Duriez, Philippe Labrune, Veronique PingaultAbstract:Waardenburg Syndrome type 4 (WS4) is a rare neural crest disorder defined by the combination of Waardenburg Syndrome (sensorineural hearing loss and pigmentation defects) and Hirschsprung disease (intestinal aganglionosis). Three genes are known to be involved in this Syndrome, that is, EDN3 (endothelin-3), EDNRB (endothelin receptor type B), and SOX10. However, 15-35% of WS4 remains unexplained at the molecular level, suggesting that other genes could be involved and/or that mutations within known genes may have escaped previous screenings. Here, we searched for deletions within recently identified SOX10 regulatory sequences and describe the first characterization of a WS4 patient presenting with a large deletion encompassing three of these enhancers. Analysis of the breakpoint region suggests a complex rearrangement involving three Alu sequences that could be mediated by a FosTes/MMBIR replication mechanism. Taken together with recent reports, our results demonstrate that the disruption of highly conserved non-coding elements located within or at a long distance from the coding sequences of key genes can result in several neurocristopathies. This opens up new routes to the molecular dissection of neural crest disorders.
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Identification and functional analysis of SOX10 missense mutations in different subtypes of Waardenburg Syndrome.
Human Mutation, 2011Co-Authors: Asma Chaoui, Veronique Pingault, Michel Goossens, Renaud Touraine, Viviane Baral, Yuli Watanabe, Nadege BondurandAbstract:Waardenburg Syndrome (WS) is a rare disorder characterized by pigmentation defects and sensorineural deafness, classified into four clinical subtypes, WS1-S4. Whereas the absence of additional features characterizes WS2, association with Hirschsprung disease defines WS4. WS is genetically heterogeneous, with six genes already identified, including SOX10. About 50 heterozygous SOX10 mutations have been described in patients presenting with WS2 or WS4, with or without myelination defects of the peripheral and central nervous system (PCWH, Peripheral demyelinating neuropathy-Central dysmyelinating leukodystrophy-Waardenburg Syndrome-Hirschsprung disease, or PCW, PCWH without HD). The majority are truncating mutations that most often remove the main functional domains of the protein. Only three missense mutations have been thus far reported. In the present study, novel SOX10 missense mutations were found in 11 patients and were examined for effects on SOX10 characteristics and functions. The mutations were associated with various phenotypes, ranging from WS2 to PCWH. All tested mutations were found to be deleterious. Some mutants presented with partial cytoplasmic redistribution, some lost their DNA-binding and/or transactivation capabilities on various tissue-specific target genes. Intriguingly, several mutants were redistributed in nuclear foci. Whether this phenomenon is a cause or a consequence of mutation-associated pathogenicity remains to be determined, but this observation could help to identify new SOX10 modes of action.
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Review and update of mutations causing Waardenburg Syndrome
Human Mutation, 2010Co-Authors: Veronique Pingault, Dorothée Ente, Florence Dastot-le Moal, Michel Goossens, Sandrine Marlin, Nadege BondurandAbstract:Waardenburg Syndrome (WS) is characterized by the association of pigmentation abnormalities, including depigmented patches of the skin and hair, vivid blue eyes or heterochromia irides, and sensorineural hearing loss. However, other features such as dystopia canthorum, musculoskeletal abnormalities of the limbs, Hirschsprung disease, or neurological defects are found in subsets of patients and used for the clinical classification of WS. Six genes are involved in this Syndrome: PAX3 (encoding the paired box 3 transcription factor), MITF (microphthalmia-associated transcription factor), EDN3 (endothelin 3), EDNRB (endothelin receptor type B), SOX10 (encoding the Sry bOX10 transcription factor), and SNAI2 (snail homolog 2), with different frequencies. In this review we provide an update on all WS genes and set up mutation databases, summarize molecular and functional data available for each of them, and discuss the applications in diagnostics and genetic counseling.
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Deletions at the SOX10 gene locus cause Waardenburg Syndrome types 2 and 4.
American Journal of Human Genetics, 2007Co-Authors: Nadege Bondurand, Florence Dastot-le Moal, Sandrine Marlin, Viviane Baral, Laure Stanchina, Nathalie Collot, Tania Attie-bitach, Irina Giurgea, Laurent Skopinski, William ReardonAbstract:Waardenburg Syndrome (WS) is an auditory-pigmentary disorder that exhibits varying combinations of sensorineural hearing loss and abnormal pigmentation of the hair and skin. Depending on additional symptoms, WS is classified into four subtypes, WS1-WS4. Absence of additional features characterizes WS2. The association of facial dysmorphic features defines WS1 and WS3, whereas the association with Hirschsprung disease (aganglionic megacolon) characterizes WS4, also called "Waardenburg-Hirschsprung disease." Mutations within the genes MITF and SNAI2 have been identified in WS2, whereas mutations of EDN3, EDNRB, and SOX10 have been observed in patients with WS4. However, not all cases are explained at the molecular level, which raises the possibility that other genes are involved or that some mutations within the known genes are not detected by commonly used genotyping methods. We used a combination of semiquantitative fluorescent multiplex polymerase chain reaction and fluorescent in situ hybridization to search for SOX10 heterozygous deletions. We describe the first characterization of SOX10 deletions in patients presenting with WS4. We also found SOX10 deletions in WS2 cases, making SOX10 a new gene of WS2. Interestingly, neurological phenotypes reminiscent of that observed in WS4 (PCWH Syndrome [peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, WS, and Hirschsprung disease]) were observed in some WS2-affected patients with SOX10 deletions. This study further characterizes the molecular complexity and the close relationship that links the different subtypes of WS.
Sinead M Murphy - One of the best experts on this subject based on the ideXlab platform.
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Waardenburg Syndrome a rare cause of inherited neuropathy due to sox10 mutation
Journal of The Peripheral Nervous System, 2017Co-Authors: Petya Bogdanovamihaylova, Michael D Alexander, Raymond P Murphy, Sinead M MurphyAbstract:Waardenburg Syndrome (WS) is a rare disorder comprising sensorineural deafness and pigmentation abnormalities. Four distinct subtypes are defined based on the presence or absence of additional symptoms. Mutations in six genes have been described in WS. SOX10 mutations are usually associated with a more severe phenotype of WS with peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, and Hirschsprung disease. Here we report a 32-year-old man with a novel heterozygous missense variant in SOX10 gene, who presented with congenital deafness, Hirschsprung disease, iris heterochromia, foot deformity, and intermediate conduction velocity length-dependent sensorimotor neuropathy. This case highlights that the presence of other non-neuropathic features in a patient with presumed hereditary neuropathy should alert the clinician to possible atypical rare causes.
Andrew P Read - One of the best experts on this subject based on the ideXlab platform.
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chromosome 13q deletion with Waardenburg Syndrome further evidence for a gene involved in neural crest function on 13q
Journal of Medical Genetics, 1995Co-Authors: G. Van Camp, M N Van Thienen, I Handig, Andrew P Read, Lindsay A Farrer, Clinton T. Baldwin, Aubrey Milunsky, Maryse BonduelleAbstract:Waardenburg Syndrome (WS) is an autosomal dominant disorder characterised by pigmentary abnormalities and sensorineural deafness. It is subcategorised into type 1 (WS1) and type 2 (WS2) on the basis of the presence (WS1) or absence (WS2) of dystopia canthorum. WS1 is always caused by mutations in the PAX3 gene, whereas WS2 is caused by mutations in the microphthalmia (MITF) gene in some but not all families. An association of WS symptoms with Hirschsprung disease (HSCR) has been reported in many families. We report here a patient with characteristics of WS2 and a de novo interstitial deletion of chromosome 13q. We also describe a family with two sibs who have both WS2 and HSCR. In this family, all possible genes for WS and HSCR, but not chromosome 13q, could be excluded. As an association between chromosome 13q and HSCR/WS has been reported previously, these data suggest that there is a gene on chromosome 13q that is responsible for WS or HSCR or both.
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Waardenburg Syndrome type ii phenotypic findings and diagnostic criteria
American Journal of Medical Genetics, 1995Co-Authors: Xue Zhong Liu, Valerie Newton, Andrew P ReadAbstract:The Waardenburg Syndrome (WS) consists of at least two distinct autosomal dominant hereditary disorders. WS Type I has been mapped to the distal part of chromosome 2q and the gene identified as PAX3. Other gene(s) are responsible for WS Type II. Mapping WS Type II requires accurate diagnosis within affected families. To establish diagnostic criteria for WS Type II, 81 individuals from 21 families with Type II WS were personally studied, and compared with 60 personally studied patients from 8 families with Type I and 253 cases of WS (Type I or II) from the literature. Sensorineural hearing loss (77%) and heterochromia iridum (47%) were the two most important diagnostic indicators for WS Type II. Both were more common in Type II than in Type I. Other clinical manifestations, such as white forelock and skin patches, were more frequent in Type I. We estimate the frequency of phenotypic traits and propose diagnostic criteria for WS Type II. In practice, a diagnosis of WS Type II can be made with confidence given a family history of congenital hearing loss and pigmentary disorders, where individuals have been accurately measured for ocular distances to exclude dystopia canthorum.
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Waardenburg Syndrome type 2 caused by mutations in the human microphthalmia mitf gene
Nature Genetics, 1994Co-Authors: Mayada Tassabehji, Valeria E Newton, Andrew P ReadAbstract:Waardenburg Syndrome type 2 (WS2) is a dominantly inherited Syndrome of hearing loss and pigmentary disturbances. We recently mapped a WS2 gene to chromosome 3p12.3-p14.1 and proposed as a candidate gene MITF, the human homologue of the mouse microphthalmia (mi) gene. This encodes a putative basic-helix-loop-helix-leucine zipper transcription factor expressed in adult skin and in embryonic retina, otic vesicle and hair follicles. Mice carrying mi mutations show reduced pigmentation of the eyes and coat, and with some alleles, microphthalmia, hearing loss, osteopetrosis and mast cell defects. Here we show that affected individuals in two WS2 families have mutations affecting splice sites in the MITF gene.
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a gene for Waardenburg Syndrome type 2 maps close to the human homologue of the microphthalmia gene at chromosome 3p12 p14 1
Nature Genetics, 1994Co-Authors: A Hughes, Valerie Newton, Andrew P ReadAbstract:Waardenburg Syndrome (WS), an autosomal dominant Syndrome of hearing loss and pigmentary disturbances, comprises at least two separate conditions. WS type 1 is normally caused by mutations in PAX3 located at chromosome 2q35 and is distinguished clinically by minor facial malformations. We have now located a gene for WS type 2. Two families show linkage to a group of microsatellite markers located on chromosome 3p12–p14.1. D3S1261 gave a maximum lod score of 6.5 at zero recombination in one large Type 2 family. In a second, smaller family the adjacent marker D3S1210 gave a lod of 2.05 at zero recombination. Interestingly, the human homologue (MITF) of the mouse microphthalmia gene, a good candidate at the phenotypic level, has recently been mapped to 3p12.3–p14.4.
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pax3 gene structure and mutations close analogies between Waardenburg Syndrome and the splotch mouse
Human Molecular Genetics, 1994Co-Authors: May Tassabehji, Valerie Newton, K Leverton, K Turnbull, E Seemanova, J Kunze, Karl Sperling, T Strachan, Andrew P ReadAbstract:The human PAX3 gene contains a paired box and a paired-type homeobox, and is believed to play a role in pattern formation in the embryo. We describe the exon-intron structure of the homeobox-containing part of PAX3, complementing earlier descriptions of the 5' part of the gene. Mutations in PAX3 have been described in patients with Type 1 Waardenburg Syndrome, who have hearing loss and pigmentary abnormalities, while Splotch mice have mutations in the homologous mouse Pax-3 gene. We describe a series of patients who have previously unidentified PAX3 mutations. These include a chromosomal deletion, a splice-site mutation and an amino acid substitution which closely correspond to the molecular changes seen in the Splotch-retarded, Splotch and Splotch-delayed mouse mutants respectively. These mutations confirm that Waardenburg Syndrome is produced by gene dosage effects and show that the phenotypic differences between Splotch mice and humans with Waardenburg Syndrome are caused by differences in genetic background rather than different primary effects of the mutations.
Michel Goossens - One of the best experts on this subject based on the ideXlab platform.
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Alu-mediated deletion of SOX10 regulatory elements in Waardenburg Syndrome type 4.
European Journal of Human Genetics, 2012Co-Authors: Nadege Bondurand, Michel Goossens, Virginie Fouquet, Viviane Baral, Laure Lecerf, Natalie Loundon, Benedicte Duriez, Philippe Labrune, Veronique PingaultAbstract:Waardenburg Syndrome type 4 (WS4) is a rare neural crest disorder defined by the combination of Waardenburg Syndrome (sensorineural hearing loss and pigmentation defects) and Hirschsprung disease (intestinal aganglionosis). Three genes are known to be involved in this Syndrome, that is, EDN3 (endothelin-3), EDNRB (endothelin receptor type B), and SOX10. However, 15-35% of WS4 remains unexplained at the molecular level, suggesting that other genes could be involved and/or that mutations within known genes may have escaped previous screenings. Here, we searched for deletions within recently identified SOX10 regulatory sequences and describe the first characterization of a WS4 patient presenting with a large deletion encompassing three of these enhancers. Analysis of the breakpoint region suggests a complex rearrangement involving three Alu sequences that could be mediated by a FosTes/MMBIR replication mechanism. Taken together with recent reports, our results demonstrate that the disruption of highly conserved non-coding elements located within or at a long distance from the coding sequences of key genes can result in several neurocristopathies. This opens up new routes to the molecular dissection of neural crest disorders.
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screening of mitf and sox10 regulatory regions in Waardenburg Syndrome type 2
PLOS ONE, 2012Co-Authors: Viviane Baral, Michel Goossens, Sandrine Marlin, Asma Chaoui, Yuli Watanabe, Tania Attiebitach, Veronique PingaultAbstract:Waardenburg Syndrome (WS) is a rare auditory-pigmentary disorder that exhibits varying combinations of sensorineural hearing loss and pigmentation defects. Four subtypes are clinically defined based on the presence or absence of additional symptoms. WS type 2 (WS2) can result from mutations within the MITF or SOX10 genes; however, 70% of WS2 cases remain unexplained at the molecular level, suggesting that other genes might be involved and/or that mutations within the known genes escaped previous screenings. The recent identification of a deletion encompassing three of the SOX10 regulatory elements in a patient presenting with another WS subtype, WS4, defined by its association with Hirschsprung disease, led us to search for deletions and point mutations within the MITF and SOX10 regulatory elements in 28 yet unexplained WS2 cases. Two nucleotide variations were identified: one in close proximity to the MITF distal enhancer (MDE) and one within the U1 SOX10 enhancer. Functional analyses argued against a pathogenic effect of these variations, suggesting that mutations within regulatory elements of WS genes are not a major cause of this neurocristopathy.
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Identification and functional analysis of SOX10 missense mutations in different subtypes of Waardenburg Syndrome.
Human Mutation, 2011Co-Authors: Asma Chaoui, Veronique Pingault, Michel Goossens, Renaud Touraine, Viviane Baral, Yuli Watanabe, Nadege BondurandAbstract:Waardenburg Syndrome (WS) is a rare disorder characterized by pigmentation defects and sensorineural deafness, classified into four clinical subtypes, WS1-S4. Whereas the absence of additional features characterizes WS2, association with Hirschsprung disease defines WS4. WS is genetically heterogeneous, with six genes already identified, including SOX10. About 50 heterozygous SOX10 mutations have been described in patients presenting with WS2 or WS4, with or without myelination defects of the peripheral and central nervous system (PCWH, Peripheral demyelinating neuropathy-Central dysmyelinating leukodystrophy-Waardenburg Syndrome-Hirschsprung disease, or PCW, PCWH without HD). The majority are truncating mutations that most often remove the main functional domains of the protein. Only three missense mutations have been thus far reported. In the present study, novel SOX10 missense mutations were found in 11 patients and were examined for effects on SOX10 characteristics and functions. The mutations were associated with various phenotypes, ranging from WS2 to PCWH. All tested mutations were found to be deleterious. Some mutants presented with partial cytoplasmic redistribution, some lost their DNA-binding and/or transactivation capabilities on various tissue-specific target genes. Intriguingly, several mutants were redistributed in nuclear foci. Whether this phenomenon is a cause or a consequence of mutation-associated pathogenicity remains to be determined, but this observation could help to identify new SOX10 modes of action.
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Review and update of mutations causing Waardenburg Syndrome
Human Mutation, 2010Co-Authors: Veronique Pingault, Dorothée Ente, Florence Dastot-le Moal, Michel Goossens, Sandrine Marlin, Nadege BondurandAbstract:Waardenburg Syndrome (WS) is characterized by the association of pigmentation abnormalities, including depigmented patches of the skin and hair, vivid blue eyes or heterochromia irides, and sensorineural hearing loss. However, other features such as dystopia canthorum, musculoskeletal abnormalities of the limbs, Hirschsprung disease, or neurological defects are found in subsets of patients and used for the clinical classification of WS. Six genes are involved in this Syndrome: PAX3 (encoding the paired box 3 transcription factor), MITF (microphthalmia-associated transcription factor), EDN3 (endothelin 3), EDNRB (endothelin receptor type B), SOX10 (encoding the Sry bOX10 transcription factor), and SNAI2 (snail homolog 2), with different frequencies. In this review we provide an update on all WS genes and set up mutation databases, summarize molecular and functional data available for each of them, and discuss the applications in diagnostics and genetic counseling.
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interaction among sox10 pax3 and mitf three genes altered in Waardenburg Syndrome
Human Molecular Genetics, 2000Co-Authors: Nadege Bondurand, Veronique Pingault, Derk E Goerich, N Lemort, Elisabeth Sock, Cedric Le Caignec, Michael Wegner, Michel GoossensAbstract:Waardenburg Syndrome (WS) is an autosomal dominant disorder with an incidence of 1 in 40 000 that manifests with sensorineural deafness and pigmentation defects. It is classified into four types depending on the presence or absence of additional symptoms. WS1 and WS3 are due to mutations in the PAX3 gene whereas some WS2 cases are associated with mutations in the microphthalmia-associated transcription factor (MITF) gene. The WS4 phenotype can result from mutations in the endothelin-B receptor gene (EDNRB), in the gene for its ligand, endothelin-3 (EDN3), or in the SOX10 gene. PAX3 has been shown to regulate MITF gene expression. The recent implication of SOX10 in WS4 prompted us to test whether this transcription factor, known to cooperate in vitro with PAX3, is also able to regulate expression from the MITF promoter. Here we show that SOX10, in synergy with PAX3, strongly activates MITF expression in transfection assays. Analyses revealed that PAX3 and SOX10 interact directly by binding to a proximal region of the MITF promoter containing binding sites for both factors. Moreover, SOX10 or PAX3 mutant proteins fail to transactivate this promoter, providing further evidence that the two genes act in concert to directly regulate expression of MITF. In situ hybridization experiments carried out in the dominant megacolon (DOM:) mouse, confirmed that SOX10 dysfunction impairs MITF: expression as well as melanocytic development and survival. These experiments, which demonstrate an interaction between three of the genes that are altered in WS, could explain the auditory-pigmentary symptoms of this disease.
