The Experts below are selected from a list of 138 Experts worldwide ranked by ideXlab platform
Michael J Dixon - One of the best experts on this subject based on the ideXlab platform.
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periderm life cycle and function during orofacial and epidermal development
Seminars in Cell & Developmental Biology, 2017Co-Authors: Nigel L Hammond, Jill Dixon, Michael J DixonAbstract:Development of the secondary palate involves a complex series of embryonic events which, if disrupted, result in the common congenital anomaly cleft palate. The secondary palate forms from paired palatal shelves which grow initially vertically before elevating to a horizontal position above the tongue and fusing together in the midline via the medial edge epithelia. As the epithelia of the vertical palatal shelves are in contact with the mandibular and lingual epithelia, pathological fusions between the palate and the mandible and/or the tongue must be prevented. This function is mediated by the single cell layered periderm which forms in a distinct and reproducible pattern early in embryogenesis, exhibits highly polarised expression of adhesion complexes, and is shed from the outer surface as the epidermis acquires its barrier function. Disruption of periderm formation and/or function underlies a series of birth defects that exhibit multiple inter-epithelial adhesions including the autosomal dominant Popliteal Pterygium Syndrome and the autosomal recessive cocoon Syndrome and Bartsocas Papas Syndrome. Genetic analyses of these conditions have shown that IRF6, IKKA, SFN, RIPK4 and GRHL3, all of which are under the transcriptional control of p63, play a key role in periderm formation. Despite these observations, the medial edge epithelia must rapidly acquire the capability to fuse if the palatal shelves are not to remain cleft. This process is driven by TGFβ3-mediated, down-regulation of p63 in the medial edge epithelia which allows periderm migration out of the midline epithelial seam and reduces the proliferative potential of the midline epithelial seam thereby preventing cleft palate. Together, these findings indicate that periderm plays a transient but fundamental role during embryogenesis in preventing pathological adhesion between intimately apposed, adhesion-competent epithelia.
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Integration of IRF6 and Jagged2 signalling is essential for controlling palatal adhesion and fusion competence
Human molecular genetics, 2009Co-Authors: Rebecca J Richardson, Jill Dixon, Rulang Jiang, Michael J DixonAbstract:In mammals, adhesion and fusion of the palatal shelves are essential mechanisms during the development of the secondary palate; failure of these processes leads to the congenital anomaly, cleft palate. The mechanisms that prevent pathological adhesion between the oral and palatal epithelia while permitting adhesion and subsequent fusion of the palatal shelves via their medial edge epithelia remain obscure. In humans, mutations in the transcription factor interferon regulatory factor 6 (IRF6) underlie Van der Woude Syndrome and Popliteal Pterygium Syndrome. Recently, we have demonstrated that mice homozygous for a mutation in Irf6 exhibit abnormalities of epithelial differentiation that results in cleft palate as a consequence of adhesion between the palatal shelves and the tongue. In the current paper, we demonstrate that Irf6 is essential for oral epithelial differentiation and that IRF6 and the Notch ligand Jagged2 function in convergent molecular pathways during this process. We further demonstrate that IRF6 plays a key role in the formation and maintenance of the oral periderm, spatio-temporal regulation of which is essential for ensuring appropriate palatal adhesion.
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missense mutations that cause van der woude Syndrome and Popliteal Pterygium Syndrome affect the dna binding and transcriptional activation functions of irf6
Human Molecular Genetics, 2009Co-Authors: Hayley J Little, Brian C Schutte, Nicholas K Rorick, Saimon Malhotra, Ling I Su, Clair Baldock, Thomas A Jowitt, Lokesh Gakhar, Ramaswamy Subramanian, Michael J DixonAbstract:Cleft lip and cleft palate (CLP) are common disorders that occur either as part of a Syndrome, where structures other than the lip and palate are affected, or in the absence of other anomalies. Van der Woude Syndrome (VWS) and Popliteal Pterygium Syndrome (PPS) are autosomal dominant disorders characterized by combinations of cleft lip, CLP, lip pits, skin-folds, syndactyly and oral adhesions which arise as the result of mutations in interferon regulatory factor 6 (IRF6). IRF6 belongs to a family of transcription factors that share a highly conserved N-terminal, DNA-binding domain and a less well-conserved protein-binding domain. To date, mutation analyses have suggested a broad genotype–phenotype correlation in which missense and nonsense mutations occurring throughout IRF6 may cause VWS; in contrast, PPS-causing mutations are highly associated with the DNA-binding domain, and appear to preferentially affect residues that are predicted to interact directly with the DNA. Nevertheless, this genotype–phenotype correlation is based on the analysis of structural models rather than on the investigation of the DNA-binding properties of IRF6. Moreover, the effects of mutations in the protein interaction domain have not been analysed. In the current investigation, we have determined the sequence to which IRF6 binds and used this sequence to analyse the effect of VWS- and PPS-associated mutations in the DNA-binding domain of IRF6. In addition, we have demonstrated that IRF6 functions as a co-operative transcriptional activator and that mutations in the protein interaction domain of IRF6 disrupt this activity.
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Irf6 is a key determinant of the keratinocyte proliferation-differentiation switch
Nature Genetics, 2006Co-Authors: Rebecca J Richardson, Jill Dixon, Saimon Malhotra, Matthew J Hardman, Lynnette Knowles, Ray P Boot-handford, Paul Shore, Alan Whitmarsh, Michael J DixonAbstract:The epidermis is a highly organized structure, the integrity of which is central to the protection of an organism^ 1 . Development and subsequent maintenance of this tissue depends critically on the intricate balance between proliferation and differentiation of a resident stem cell population^ 1 , 2 ; however, the signals controlling the proliferation-differentiation switch in vivo remain elusive^ 3 . Here, we show that mice carrying a homozygous missense mutation in interferon regulatory factor 6 ( Irf6 ), the homolog of the gene mutated in the human congenital disorders Van der Woude Syndrome and Popliteal Pterygium Syndrome, have a hyperproliferative epidermis that fails to undergo terminal differentiation, resulting in soft tissue fusions. We further demonstrate that mice that are compound heterozygotes for mutations in Irf6 and the gene encoding the cell cycle regulator protein stratifin (Sfn; also known as 14-3-3σ) show similar defects of keratinizing epithelia. Our results indicate that Irf6 is a key determinant of the keratinocyte proliferation-differentiation switch and that Irf6 and Sfn interact genetically in this process.
Sherri Bale - One of the best experts on this subject based on the ideXlab platform.
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Prevalence and nonrandom distribution of exonic mutations in interferon regulatory factor 6 in 307 families with Van der Woude Syndrome and 37 families with Popliteal Pterygium Syndrome
Genetics in Medicine, 2009Co-Authors: Renata L L Ferreira De Lima, Shinji Kondo, Sarah A Hoper, Michella Ghassibe, Margaret E Cooper, Nicholas K Rorick, Lori Katz, Mary L Marazita, John Compton, Sherri BaleAbstract:Purpose: Interferon regulatory factor 6 encodes a member of the IRF family of transcription factors. Mutations in interferon regulatory factor 6 cause Van der Woude and Popliteal Pterygium Syndrome, two related orofacial clefting disorders. Here, we compared and contrasted the frequency and distribution of exonic mutations in interferon regulatory factor 6 between two large geographically distinct collections of families with Van der Woude and between one collection of families with Popliteal Pterygium Syndrome. Methods: We performed direct sequence analysis of interferon regulatory factor 6 exons on samples from three collections, two with Van der Woude and one with Popliteal Pterygium Syndrome. Results: We identified mutations in interferon regulatory factor 6 exons in 68% of families in both Van der Woude collections and in 97% of families with Popliteal Pterygium Syndrome. In sum, 106 novel disease-causing variants were found. The distribution of mutations in the interferon regulatory factor 6 exons in each collection was not random; exons 3, 4, 7, and 9 accounted for 80%. In the Van der Woude collections, the mutations were evenly divided between protein truncation and missense, whereas most mutations identified in the Popliteal Pterygium Syndrome collection were missense. Further, the missense mutations associated with Popliteal Pterygium Syndrome were localized significantly to exon 4, at residues that are predicted to bind directly to DNA. Conclusion: The nonrandom distribution of mutations in the interferon regulatory factor 6 exons suggests a two-tier approach for efficient mutation screens for interferon regulatory factor 6. The type and distribution of mutations are consistent with the hypothesis that Van der Woude is caused by haploinsufficiency of interferon regulatory factor 6. On the other hand, the distribution of Popliteal Pterygium Syndrome-associated mutations suggests a different, though not mutually exclusive, effect on interferon regulatory factor 6 function.
Shinji Kondo - One of the best experts on this subject based on the ideXlab platform.
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Prevalence and nonrandom distribution of exonic mutations in interferon regulatory factor 6 in 307 families with Van der Woude Syndrome and 37 families with Popliteal Pterygium Syndrome
Genetics in Medicine, 2009Co-Authors: Renata L L Ferreira De Lima, Shinji Kondo, Sarah A Hoper, Michella Ghassibe, Margaret E Cooper, Nicholas K Rorick, Lori Katz, Mary L Marazita, John Compton, Sherri BaleAbstract:Purpose: Interferon regulatory factor 6 encodes a member of the IRF family of transcription factors. Mutations in interferon regulatory factor 6 cause Van der Woude and Popliteal Pterygium Syndrome, two related orofacial clefting disorders. Here, we compared and contrasted the frequency and distribution of exonic mutations in interferon regulatory factor 6 between two large geographically distinct collections of families with Van der Woude and between one collection of families with Popliteal Pterygium Syndrome. Methods: We performed direct sequence analysis of interferon regulatory factor 6 exons on samples from three collections, two with Van der Woude and one with Popliteal Pterygium Syndrome. Results: We identified mutations in interferon regulatory factor 6 exons in 68% of families in both Van der Woude collections and in 97% of families with Popliteal Pterygium Syndrome. In sum, 106 novel disease-causing variants were found. The distribution of mutations in the interferon regulatory factor 6 exons in each collection was not random; exons 3, 4, 7, and 9 accounted for 80%. In the Van der Woude collections, the mutations were evenly divided between protein truncation and missense, whereas most mutations identified in the Popliteal Pterygium Syndrome collection were missense. Further, the missense mutations associated with Popliteal Pterygium Syndrome were localized significantly to exon 4, at residues that are predicted to bind directly to DNA. Conclusion: The nonrandom distribution of mutations in the interferon regulatory factor 6 exons suggests a two-tier approach for efficient mutation screens for interferon regulatory factor 6. The type and distribution of mutations are consistent with the hypothesis that Van der Woude is caused by haploinsufficiency of interferon regulatory factor 6. On the other hand, the distribution of Popliteal Pterygium Syndrome-associated mutations suggests a different, though not mutually exclusive, effect on interferon regulatory factor 6 function.
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mutations in irf6 cause van der woude and Popliteal Pterygium Syndromes
Nature Genetics, 2002Co-Authors: Shinji Kondo, Brian C Schutte, Rebecca J Richardson, Bryan C Bjork, Alexandra S Knight, Yoriko Watanabe, Emma Howard, Renata Ferreira L L De Lima, Sandra Daackhirsch, Achim SanderAbstract:Interferon regulatory factor 6 (IRF6) belongs to a family of nine transcription factors that share a highly conserved helix–turn–helix DNA-binding domain and a less conserved protein-binding domain. Most IRFs regulate the expression of interferon-α and -β after viral infection1, but the function of IRF6 is unknown. The gene encoding IRF6 is located in the critical region for the Van der Woude Syndrome (VWS; OMIM 119300) locus at chromosome 1q32–q41 (refs 2,3). The disorder is an autosomal dominant form of cleft lip and palate with lip pits4, and is the most common syndromic form of cleft lip or palate. Popliteal Pterygium Syndrome (PPS; OMIM 119500) is a disorder with a similar orofacial phenotype that also includes skin and genital anomalies5. Phenotypic overlap6 and linkage data7 suggest that these two disorders are allelic. We found a nonsense mutation in IRF6 in the affected twin of a pair of monozygotic twins who were discordant for VWS. Subsequently, we identified mutations in IRF6 in 45 additional unrelated families affected with VWS and distinct mutations in 13 families affected with PPS. Expression analyses showed high levels of Irf6 mRNA along the medial edge of the fusing palate, tooth buds, hair follicles, genitalia and skin. Our observations demonstrate that haploinsufficiency of IRF6 disrupts orofacial development and are consistent with dominant-negative mutations disturbing development of the skin and genitalia.
Nicholas K Rorick - One of the best experts on this subject based on the ideXlab platform.
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Prevalence and nonrandom distribution of exonic mutations in interferon regulatory factor 6 in 307 families with Van der Woude Syndrome and 37 families with Popliteal Pterygium Syndrome
Genetics in Medicine, 2009Co-Authors: Renata L L Ferreira De Lima, Shinji Kondo, Sarah A Hoper, Michella Ghassibe, Margaret E Cooper, Nicholas K Rorick, Lori Katz, Mary L Marazita, John Compton, Sherri BaleAbstract:Purpose: Interferon regulatory factor 6 encodes a member of the IRF family of transcription factors. Mutations in interferon regulatory factor 6 cause Van der Woude and Popliteal Pterygium Syndrome, two related orofacial clefting disorders. Here, we compared and contrasted the frequency and distribution of exonic mutations in interferon regulatory factor 6 between two large geographically distinct collections of families with Van der Woude and between one collection of families with Popliteal Pterygium Syndrome. Methods: We performed direct sequence analysis of interferon regulatory factor 6 exons on samples from three collections, two with Van der Woude and one with Popliteal Pterygium Syndrome. Results: We identified mutations in interferon regulatory factor 6 exons in 68% of families in both Van der Woude collections and in 97% of families with Popliteal Pterygium Syndrome. In sum, 106 novel disease-causing variants were found. The distribution of mutations in the interferon regulatory factor 6 exons in each collection was not random; exons 3, 4, 7, and 9 accounted for 80%. In the Van der Woude collections, the mutations were evenly divided between protein truncation and missense, whereas most mutations identified in the Popliteal Pterygium Syndrome collection were missense. Further, the missense mutations associated with Popliteal Pterygium Syndrome were localized significantly to exon 4, at residues that are predicted to bind directly to DNA. Conclusion: The nonrandom distribution of mutations in the interferon regulatory factor 6 exons suggests a two-tier approach for efficient mutation screens for interferon regulatory factor 6. The type and distribution of mutations are consistent with the hypothesis that Van der Woude is caused by haploinsufficiency of interferon regulatory factor 6. On the other hand, the distribution of Popliteal Pterygium Syndrome-associated mutations suggests a different, though not mutually exclusive, effect on interferon regulatory factor 6 function.
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missense mutations that cause van der woude Syndrome and Popliteal Pterygium Syndrome affect the dna binding and transcriptional activation functions of irf6
Human Molecular Genetics, 2009Co-Authors: Hayley J Little, Brian C Schutte, Nicholas K Rorick, Saimon Malhotra, Ling I Su, Clair Baldock, Thomas A Jowitt, Lokesh Gakhar, Ramaswamy Subramanian, Michael J DixonAbstract:Cleft lip and cleft palate (CLP) are common disorders that occur either as part of a Syndrome, where structures other than the lip and palate are affected, or in the absence of other anomalies. Van der Woude Syndrome (VWS) and Popliteal Pterygium Syndrome (PPS) are autosomal dominant disorders characterized by combinations of cleft lip, CLP, lip pits, skin-folds, syndactyly and oral adhesions which arise as the result of mutations in interferon regulatory factor 6 (IRF6). IRF6 belongs to a family of transcription factors that share a highly conserved N-terminal, DNA-binding domain and a less well-conserved protein-binding domain. To date, mutation analyses have suggested a broad genotype–phenotype correlation in which missense and nonsense mutations occurring throughout IRF6 may cause VWS; in contrast, PPS-causing mutations are highly associated with the DNA-binding domain, and appear to preferentially affect residues that are predicted to interact directly with the DNA. Nevertheless, this genotype–phenotype correlation is based on the analysis of structural models rather than on the investigation of the DNA-binding properties of IRF6. Moreover, the effects of mutations in the protein interaction domain have not been analysed. In the current investigation, we have determined the sequence to which IRF6 binds and used this sequence to analyse the effect of VWS- and PPS-associated mutations in the DNA-binding domain of IRF6. In addition, we have demonstrated that IRF6 functions as a co-operative transcriptional activator and that mutations in the protein interaction domain of IRF6 disrupt this activity.
Renata Ferreira L L De Lima - One of the best experts on this subject based on the ideXlab platform.
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Prevalence and nonrandom distribution of exonic mutations in interferon regulatory factor 6 in 307 families with Van der Woude Syndrome and 37 families with Popliteal Pterygium Syndrome
Lippincott Williams & Wilkins, 2009Co-Authors: Renata Ferreira L L De Lima, Hoper, Sarah A., Ghassibe Michella, Cooper, Margaret E., Rorick, Nicholas K., Kondo Shinji, Katz Lori, Marazita, Mary L., Compton John, Bale SherriAbstract:Purpose: Interferon regulatory factor 6 encodes a member of the IRF family of transcription factors. Mutations in interferon regulatory factor 6 cause Van der Woude and Popliteal Pterygium Syndrome, two related orofacial clefting disorders. Here, we compared and contrasted the frequency and distribution of exonic Mutations in interferon regulatory factor 6 between two large geographically distinct collections of families with Van der Woude and between one collection of families with Popliteal Pterygium Syndrome. Methods: We performed direct sequence analysis of interferon regulatory factor 6 exons oil samples from three collections, two with Van der Woude and one with Popliteal Pterygium Syndrome. Results: We identified mutations in interferon regulatory factor 6 exons in 68% of families in both Van der Woude collections and in 97% of families with Popliteal Pterygium Syndrome. In sum, 106 novel disease-causing variants were found. The distribution of mutations in the interferon regulatory factor 6 exons in each collection was not random; exons 3, 4, 7, and 9 accounted for 80%. In the Van der Woude collections, the mutations were evenly divided between protein truncation and missense, whereas most mutations identified in the Popliteal Pterygium Syndrome collection were missense. Further, the missense mutations associated with Popliteal Pterygium Syndrome were localized significantly to exon 4, at residues that are predicted to bind directly to DNA. Conclusion: The nonrandom distribution of mutations in the interferon regulatory factor 6 exons suggests a two-tier approach for efficient mutation screens for interferon regulatory factor 6. The type and distribution of mutations are consistent with the hypothesis that Van der Woude is caused by haploinsufficiency of interferon regulatory factor 6. Oil the other hand, the distribution of Popliteal Pterygium Syndrome-associated mutations suggests a different, though not mutually exclusive, effect oil interferon regulatory factor 6 function. Genet Med 2009:11(4):241-247
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Prevalence and nonrandom distribution of exonic mutations in interferon regulatory factor 6 in 307 families with Van der Woude Syndrome and 37 families with Popliteal Pterygium Syndrome
LIPPINCOTT WILLIAMS & WILKINS, 2009Co-Authors: Renata Ferreira L L De Lima, Hoper, Sarah A., Ghassibe Michella, Cooper, Margaret E., Rorick, Nicholas K., Kondo Shinji, Katz Lori, Marazita, Mary L., Compton John, Bale SherriAbstract:Purpose: Interferon regulatory factor 6 encodes a member of the IRF family of transcription factors. Mutations in interferon regulatory factor 6 cause Van der Woude and Popliteal Pterygium Syndrome, two related orofacial clefting disorders. Here, we compared and contrasted the frequency and distribution of exonic Mutations in interferon regulatory factor 6 between two large geographically distinct collections of families with Van der Woude and between one collection of families with Popliteal Pterygium Syndrome. Methods: We performed direct sequence analysis of interferon regulatory factor 6 exons oil samples from three collections, two with Van der Woude and one with Popliteal Pterygium Syndrome. Results: We identified mutations in interferon regulatory factor 6 exons in 68% of families in both Van der Woude collections and in 97% of families with Popliteal Pterygium Syndrome. In sum, 106 novel disease-causing variants were found. The distribution of mutations in the interferon regulatory factor 6 exons in each collection was not random; exons 3, 4, 7, and 9 accounted for 80%. In the Van der Woude collections, the mutations were evenly divided between protein truncation and missense, whereas most mutations identified in the Popliteal Pterygium Syndrome collection were missense. Further, the missense mutations associated with Popliteal Pterygium Syndrome were localized significantly to exon 4, at residues that are predicted to bind directly to DNA. Conclusion: The nonrandom distribution of mutations in the interferon regulatory factor 6 exons suggests a two-tier approach for efficient mutation screens for interferon regulatory factor 6. The type and distribution of mutations are consistent with the hypothesis that Van der Woude is caused by haploinsufficiency of interferon regulatory factor 6. Oil the other hand, the distribution of Popliteal Pterygium Syndrome-associated mutations suggests a different, though not mutually exclusive, effect oil interferon regulatory factor 6 function. Genet Med 2009:11(4):241-247.NIH[R01-DE013513]NIH[R01-DE08559]NIH[P50-DE016215]Fonds Speciaux de Recherche-Universite catholique de LouvainFonds national de la recherche scientifique (F.N.R.S.)F.R.I.A. (Fonds pour la formation a la recherche dans l`industrie et dans l`agriculture
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mutations in irf6 cause van der woude and Popliteal Pterygium Syndromes
Nature Genetics, 2002Co-Authors: Shinji Kondo, Brian C Schutte, Rebecca J Richardson, Bryan C Bjork, Alexandra S Knight, Yoriko Watanabe, Emma Howard, Renata Ferreira L L De Lima, Sandra Daackhirsch, Achim SanderAbstract:Interferon regulatory factor 6 (IRF6) belongs to a family of nine transcription factors that share a highly conserved helix–turn–helix DNA-binding domain and a less conserved protein-binding domain. Most IRFs regulate the expression of interferon-α and -β after viral infection1, but the function of IRF6 is unknown. The gene encoding IRF6 is located in the critical region for the Van der Woude Syndrome (VWS; OMIM 119300) locus at chromosome 1q32–q41 (refs 2,3). The disorder is an autosomal dominant form of cleft lip and palate with lip pits4, and is the most common syndromic form of cleft lip or palate. Popliteal Pterygium Syndrome (PPS; OMIM 119500) is a disorder with a similar orofacial phenotype that also includes skin and genital anomalies5. Phenotypic overlap6 and linkage data7 suggest that these two disorders are allelic. We found a nonsense mutation in IRF6 in the affected twin of a pair of monozygotic twins who were discordant for VWS. Subsequently, we identified mutations in IRF6 in 45 additional unrelated families affected with VWS and distinct mutations in 13 families affected with PPS. Expression analyses showed high levels of Irf6 mRNA along the medial edge of the fusing palate, tooth buds, hair follicles, genitalia and skin. Our observations demonstrate that haploinsufficiency of IRF6 disrupts orofacial development and are consistent with dominant-negative mutations disturbing development of the skin and genitalia.