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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. 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 genes have been found to be involved or 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>. 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>. | 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. 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 genes have been found to be involved or 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>. 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>. | ||
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><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><pubmed> | 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><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><pubmed>24124047</>. | ||
There are several hypotheses how IRF6 irregularities may affect development on a molecular level derived from various animal models. 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. IRF6 also has been identified as a key determinant of keratinocyte proliferation, oral periderm formation, and its spatio-temporal regulation. | There are several hypotheses how IRF6 irregularities may affect development on a molecular level derived from various animal models. 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. IRF6 also has been identified as a key determinant of keratinocyte proliferation, oral periderm formation, and its spatio-temporal regulation. |
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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. 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 genes have been found to be involved or 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)[1], an important member of the IRF family involved in oral and maxillofacial development[2]. 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[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 non-syndromic cleft lip and/or palate[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[7]
PMID 19013452 PMID 22931925 PMID 24124047
- ↑ <pubmed>15185170</pubmed>
- ↑ <pubmed>23940636</pubmed>
- ↑ <pubmed>24124047</pubmed>
- ↑ <pubmed>21331089</pubmed>
- ↑ <pubmed>22438645</pubmed>
- ↑ <pubmed>23949966</pubmed>
- ↑ <pubmed>24124047</>. There are several hypotheses how IRF6 irregularities may affect development on a molecular level derived from various animal models. 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. IRF6 also has been identified as a key determinant of keratinocyte proliferation, oral periderm formation, and its spatio-temporal regulation. p63 activates IRF6 transcription and is....<ref><pubmed>21331089</pubmed>