Novel IRF6 mutations in Honduran Van Der Woude syndrome patients

Birkeland, Andrew C.; Larrabee, Yuna C.; Kent, David T.; Flores, Carlos; Su, Gloria H.; Lee, Joseph H.; Haddad, Joseph

doi:10.3892/mmr.2011.423

Cited by 8 publications

(1 citation statement)

References 12 publications

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“…Different mutations in the DNA-binding domain and protein-binding domain are known to disrupt the function of IRF6. Exons 3 and 4 encode the DNA-binding domain, while exons 7 and 8 encode the protein-binding domain of IRF6 ( Birkeland et al, 2011 ). The novel mutation (c.748C>T, p. R250X) was located within the SMIR protein-binding domain and led to the formation of a premature stop codon and a complete loss of the protein-binding domain ( Kondo et al, 2002 ).…”

Section: Discussionmentioning

confidence: 99%

A novel IRF6 gene mutation impacting the regulation of TGFβ2-AS1 in the TGFβ pathway: A mechanism in the development of Van der Woude syndrome

Zhao,

Cui,

Chi

et al. 2024

Front. Genet.

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Several mutations in the IRF6 gene have been identified as a causative link to VWS. In this investigation, whole-exome sequencing (WES) and Sanger sequencing of a three-generation pedigree with an autosomal-dominant inheritance pattern affected by VWS identified a unique stop-gain mutation—c.748C>T:p.R250X—in the IRF6 gene that co-segregated exclusively with the disease phenotype. Immunofluorescence analysis revealed that the IRF6-p.R250X mutation predominantly shifted its localization from the nucleus to the cytoplasm. WES and protein interaction analyses were conducted to understand this mutation’s role in the pathogenesis of VWS. Using LC-MS/MS, we found that this mutation led to a reduction in the binding of IRF6 to histone modification-associated proteins (NAA10, SNRPN, NAP1L1). Furthermore, RNA-seq results show that the mutation resulted in a downregulation of TGFβ2-AS1 expression. The findings highlight the mutation’s influence on TGFβ2-AS1 and its subsequent effects on the phosphorylation of SMAD2/3, which are critical in maxillofacial development, particularly the palate. These insights contribute to a deeper understanding of VWS’s molecular underpinnings and might inform future therapeutic strategies.

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Section: Discussionmentioning

confidence: 99%

A novel IRF6 gene mutation impacting the regulation of TGFβ2-AS1 in the TGFβ pathway: A mechanism in the development of Van der Woude syndrome

Zhao,

Cui,

Chi

et al. 2024

Front. Genet.

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Toward an orofacial gene regulatory network

Kousa

Schutte

2015

Developmental Dynamics

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Orofacial clefting is a common birth defect with significant morbidity. A panoply of candidate genes have been discovered through synergy of animal models and human genetics. Among these, variants in Interferon Regulatory Factor 6 (IRF6) cause syndromic orofacial clefting and contribute risk toward isolated cleft lip and palate (1/700 live births). Rare variants in IRF6 can lead to Van der Woude Syndrome (1/35,000 live births) and Popliteal Pterygium Syndrome (1/300,000 live births). Furthermore, IRF6 regulates GRHL3 and rare variants in this downstream target can also lead to Van der Woude Syndrome. In addition, a common variant (rs642961) in the IRF6 locus is found in 30% of the world’s population and contributes risk for isolated orofacial clefting. Biochemical studies revealed that rs642961 abrogates one of four AP-2alpha binding sites. Like IRF6 and GRHL3, rare variants in TFAP2A can also lead to syndromic orofacial clefting with lip pits (Branchio-oculo-facial Syndrome). The literature suggests that AP-2alpha, IRF6 and GRHL3 are part of a pathway that is essential for lip and palate development. In addition to updating the pathways, players and pursuits, this review will highlight some of the current questions in the study of orofacial clefting.

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The prevalence, penetrance, and expressivity of etiologicIRF6variants in orofacial clefts patients from sub‐Saharan Africa

Gowans

Busch

Mossey

et al. 2017

Molec Gen & Gen Med

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BackgroundOrofacial clefts are congenital malformations of the orofacial region, with a global incidence of one per 700 live births. Interferon Regulatory Factor 6 (IRF6) (OMIM:607199) gene has been associated with the etiology of both syndromic and nonsyndromic orofacial clefts. The aim of this study was to show evidence of potentially pathogenic variants in IRF6 in orofacial clefts cohorts from Africa.MethodsWe carried out Sanger Sequencing on DNA from 184 patients with nonsyndromic orofacial clefts and 80 individuals with multiple congenital anomalies that presented with orofacial clefts. We sequenced all the nine exons of IRF6 as well as the 5′ and 3′ untranslated regions. In our analyses pipeline, we used various bioinformatics tools to detect and describe the potentially etiologic variants.ResultsWe observed that potentially etiologic exonic and splice site variants were nonrandomly distributed among the nine exons of IRF6, with 92% of these variants occurring in exons 4 and 7. Novel variants were also observed in both nonsyndromic orofacial clefts (p.Glu69Lys, p.Asn185Thr, c.175‐2A>C and c.1060+26C>T) and multiple congenital anomalies (p.Gly65Val, p.Lys320Asn and c.379+1G>T) patients. Our data also show evidence of compound heterozygotes that may modify phenotypes that emanate from IRF6 variants.ConclusionsThis study demonstrates that exons 4 and 7 of IRF6 are mutational ‘hotspots’ in our cohort and that IRF6 mutants‐induced orofacial clefts may be prevalent in the Africa population, however, with variable penetrance and expressivity. These observations are relevant for detection of high‐risk families as well as genetic counseling. In conclusion, we have shown that there may be a need to combine both molecular and clinical evidence in the grouping of orofacial clefts into syndromic and nonsyndromic forms.

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Novel IRF6 mutations in Honduran Van Der Woude syndrome patients

Cited by 8 publications

References 12 publications

A novel IRF6 gene mutation impacting the regulation of TGFβ2-AS1 in the TGFβ pathway: A mechanism in the development of Van der Woude syndrome

A novel IRF6 gene mutation impacting the regulation of TGFβ2-AS1 in the TGFβ pathway: A mechanism in the development of Van der Woude syndrome

Toward an orofacial gene regulatory network

The prevalence, penetrance, and expressivity of etiologicIRF6variants in orofacial clefts patients from sub‐Saharan Africa

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