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Interferon regulatory factor-6 and Cleft Lip and Palate | Interferon regulatory factor-6 and Cleft Lip and Palate | ||
Orofacial clefts such as cleft lip and/or palate are common structural birth defects with birth prevalence ranging from 1/500 to 1/2,000 in different populations | Orofacial clefts such as cleft lip and/or palate are common structural birth defects with birth prevalence ranging from 1/500 to 1/2,000 in different populations. The failure in growth of the frontonasal prominence, the paired mandibular processes, the paired maxillary processes, and the medial and lateral nasal processes in week 4, together with the failure in fusion of the lateral nasal processes with the maxillary processes, and the medial nasal processes in week 6 and 7 results in orofacial clefting of the upper lip and/or primary palate. Clefts in the secondary palate may arise due to failure in several developmental steps after week 6, such as palatal shelves elevation or migration<ref><pubmed>24124047</pubmed></ref>.Their complex etiology is not fully understood and both genetic and environmental causes have been established to be involved in cleft lip and/or palate development. Many aberrations in different genes have been found to correlate with cleft occurrence. One pivotal gene appears to be located on chromosome 1 at the 1q32 region, which encodes interferon regulatory factor-6 (IRF6)<ref><pubmed>15185170</pubmed></ref>, an important member of the IRF family involved in oral and maxillofacial development<ref><pubmed>23940636</pubmed></ref>. | ||
Mutations in IRF6 were first identified in patients suffering from Van der Woude syndrome, who often display orofacial clefts in addition to other symptoms. In several subsequent research studies SNPs in IRF6 were also detected in non-syndromic cleft lip and/or palate<ref name="PMID21331089"><pubmed>21331089</pubmed></ref>. The phenotypic heterogeneity of Van der Woude syndrome in comparison to non-syndromic cleft lip and/or palate is hypothesized to be caused by different types of mutations of IRF6 resulting in either a partially or fully nonfunctional protein<ref><pubmed>22438645</pubmed></ref>. In addition, the phenotype might be influenced by the site of mutation<ref><pubmed>23949966</pubmed></ref>. Mutations on a specific sequence variant about ten kb upstream of its transcription start site have been found to keep transcription factor AP-2α from binding and, therefore, influencing IRF6 expression<ref name="PMID21331089"/>. | Mutations in IRF6 were first identified in patients suffering from Van der Woude syndrome, who often display orofacial clefts in addition to other symptoms. In several subsequent research studies SNPs in IRF6 were also detected in some non-syndromic cleft lip and/or palate. Irregularities in IRF6, therefore, are considered risk factors for cleft lip and/or palate development<ref name="PMID21331089"><pubmed>21331089</pubmed></ref>. The phenotypic heterogeneity of Van der Woude syndrome in comparison to non-syndromic cleft lip and/or palate is hypothesized to be caused by different types of mutations of IRF6 resulting in either a partially or fully nonfunctional protein<ref><pubmed>22438645</pubmed></ref>. In addition, the phenotype might be influenced by the site of mutation<ref><pubmed>23949966</pubmed></ref>. Mutations on a specific sequence variant about ten kb upstream of its transcription start site have been found to keep transcription factor AP-2α from binding and, therefore, influencing IRF6 expression<ref name="PMID21331089"/>. | ||
Many animal models have given rise to several hypotheses about how IRF6 irregularities may affect development on a molecular level. For instance, IRF6 mutations caused a hyper-proliferative epidermis in mice. This will induce a failure of terminal differentiation in the respective epidermis and generate epithelial adhesions that can clog the oral cavity and create a cleft palate further on during development. IRF6 also has been identified as a key determinant of keratinocyte proliferation, oral periderm formation, and its spatio-temporal regulation. Additionally, IRF6 in interaction with other transcription factors has been studied widely. For example, p63 activates IRF6 transcription and is mutated in many malformation syndromes that display cleft lip and/or palate. This emphasizes IRF6's role in facial development and in the etiology of orofacial clefts<ref name="PMID21331089"/>. Studies in zebrafish and frog embryos have provided information about the interaction between IRF6 and Grainyhead-like 3 (Grhl3), which has effects on regulation of the epidermal permeability barrier and on periderm differentiation. IRF6 seems to directly active Grhl3 expression by binding to its promotor. This Grhl3 promotor binding association has also been observed in humans<ref><pubmed>22931925</pubmed></ref>. Several other hypotheses of IRF6's involvement in the etiology of cleft lip and/or palate have been proposed, however, the precise mechanisms are not known and more research is needed to fully establish these<ref><pubmed>26332872</pubmed></ref>. | |||
p63 activates IRF6 transcription and is. | |||
PMID 24124047 PMID 22931925 PMID 26332872 | |||
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Interferon regulatory factor-6 and Cleft Lip and Palate
Orofacial clefts such as cleft lip and/or palate are common structural birth defects with birth prevalence ranging from 1/500 to 1/2,000 in different populations. The failure in growth of the frontonasal prominence, the paired mandibular processes, the paired maxillary processes, and the medial and lateral nasal processes in week 4, together with the failure in fusion of the lateral nasal processes with the maxillary processes, and the medial nasal processes in week 6 and 7 results in orofacial clefting of the upper lip and/or primary palate. Clefts in the secondary palate may arise due to failure in several developmental steps after week 6, such as palatal shelves elevation or migration[1].Their complex etiology is not fully understood and both genetic and environmental causes have been established to be involved in cleft lip and/or palate development. Many aberrations in different genes have been found to correlate with cleft occurrence. One pivotal gene appears to be located on chromosome 1 at the 1q32 region, which encodes interferon regulatory factor-6 (IRF6)[2], an important member of the IRF family involved in oral and maxillofacial development[3].
Mutations in IRF6 were first identified in patients suffering from Van der Woude syndrome, who often display orofacial clefts in addition to other symptoms. In several subsequent research studies SNPs in IRF6 were also detected in some non-syndromic cleft lip and/or palate. Irregularities in IRF6, therefore, are considered risk factors for cleft lip and/or palate development[4]. The phenotypic heterogeneity of Van der Woude syndrome in comparison to non-syndromic cleft lip and/or palate is hypothesized to be caused by different types of mutations of IRF6 resulting in either a partially or fully nonfunctional protein[5]. In addition, the phenotype might be influenced by the site of mutation[6]. Mutations on a specific sequence variant about ten kb upstream of its transcription start site have been found to keep transcription factor AP-2α from binding and, therefore, influencing IRF6 expression[4].
Many animal models have given rise to several hypotheses about how IRF6 irregularities may affect development on a molecular level. For instance, IRF6 mutations caused a hyper-proliferative epidermis in mice. This will induce a failure of terminal differentiation in the respective epidermis and generate epithelial adhesions that can clog the oral cavity and create a cleft palate further on during development. IRF6 also has been identified as a key determinant of keratinocyte proliferation, oral periderm formation, and its spatio-temporal regulation. Additionally, IRF6 in interaction with other transcription factors has been studied widely. For example, p63 activates IRF6 transcription and is mutated in many malformation syndromes that display cleft lip and/or palate. This emphasizes IRF6's role in facial development and in the etiology of orofacial clefts[4]. Studies in zebrafish and frog embryos have provided information about the interaction between IRF6 and Grainyhead-like 3 (Grhl3), which has effects on regulation of the epidermal permeability barrier and on periderm differentiation. IRF6 seems to directly active Grhl3 expression by binding to its promotor. This Grhl3 promotor binding association has also been observed in humans[7]. Several other hypotheses of IRF6's involvement in the etiology of cleft lip and/or palate have been proposed, however, the precise mechanisms are not known and more research is needed to fully establish these[8].
PMID 24124047 PMID 22931925 PMID 26332872