Novel <i>IRF6</i> mutations in Chinese Han families with Van der Woude syndrome

Yu, Yang; Wan, Ya-Tao; Qin, Chuanqi; Yue, Haitang; Bian, Zhuan; He, Maoxian

doi:10.1002/mgg3.1196

Cited by 4 publications

(2 citation statements)

References 30 publications

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“…The IRF family is unified by a conserved helix-turn-helix DNA-binding domain (DBD) that is complemented by a variably conserved protein-binding region denoted as the Ski-interacting protein-like domain (SMIR). A repertoire of over 200 mutations in IRF6 , spanning missense, non-sense, frameshift, microdeletions, and splice-site mutations, has been documented in relation to VWS ( Zhao et al, 2018 ; Wang et al, 2019 ; Yu et al, 2020 ). Collectively, these mutations account for 72% of VWS diagnoses.…”

Section: Introductionmentioning

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: Introductionmentioning

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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“…Interestingly, distribution of these variations is enriched in either exon 3 and 4, which encodes the highly conserved N terminal DNA-binding domain (DBD), or in exon 7 and 9, which are in the less conserved C terminal protein-binding domain SMIR. 14,15 While missense, nonsense, frameshift, microdeletions and splicing variations in IRF6 have been reported to cause VWS, convincing genotype-phenotypic associations need further validation. 16,17 In this study, five Chinese VWS pedigrees were collected for pathogenic variations screening by whole exome sequencing (WES) and evaluated the function of variations, by observing its effects on IRF6 expression.…”

Section: Introductionmentioning

confidence: 99%

Causal Variations at IRF6 Gene Identified in Van der Woude Syndrome Pedigrees

Yang

Yin

Shi

et al. 2023

The Cleft Palate Craniofacial Journal

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The purpose of this study is to analyze the clinical characteristics of patients with Van der Woude syndrome (VWS) and to detect variations in each patient. Finally, the combination of genotype and phenotype can make a clear diagnosis of VWS patients with different phenotype penetrance. Five Chinese VWS pedigree were enrolled. Whole exome sequencing of the proband was performed, and the potential pathogenic variation was further verified by Sanger sequencing in the patient and their parents. The human mutant IRF6 coding sequence was generated from the human full-length IRF6 plasmid by site-directed mutagenesis and cloned into the GV658 vector, RT-qPCR and Western blot were used to detect the expression of IRF6. We found one de novo nonsense variation (p. Gln118Ter) and three novel missense variations (p. Gly301Glu, p. Gly267Ala, and p. Glu404Gly) co-segregated with VWS. RT-qPCR analysis revealed that p. Glu404Gly significantly reduced the expression level of IRF6 mRNA. Western blot of cell lysates confirmed that IRF6 p. Glu404Gly abundance levels were lower than those for IRF6 wild type. This discovery of the novel variation ( IRF6 p. Glu404Gly) expands the spectrum of known variations in VWS in Chinese humans. Genetic results combined with clinical phenotypes and differential diagnosis points from other diseases can make a definitive diagnosis and provide genetic counseling for families.

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Mycndeficiency underlies the development of orofacial clefts in mice and humans

Yang

Huang

et al. 2021

Human Molecular Genetics

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Non-syndromic cleft lip with or without cleft palate (NSCL/P) is the most common subphenotype of non-syndromic orofacial clefts (NSOFCs) arising from genetic and/or environmental perturbations during embryonic development. We previously identified 2p24.2 as a risk locus associated with NSCL/P in the Chinese Han population, and MYCN is a candidate risk gene in this region. To understand the potential function of MYCN in craniofacial development, we generated Wnt1-Cre;Mycnflox/flox mice that exhibited cleft palate, microglossia, and micrognathia, resembling the Pierre Robin sequence (PRS) in humans. Further analyses indicated that the cleft palate was secondary to the delayed elevation of palatal shelves caused by micrognathia. The micrognathia resulted from impaired chondrogenic differentiation in Merkel’s cartilage, which limited tongue development, leading to microglossia. In terms of mechanism, Mycn deficiency in cranial neural crest cells (CNCCs) downregulated Sox9 expression by inhibiting Wnt5a in a CNCC-derived chondrogenic lineage in Merkel’s cartilage. To investigate whether MYCN deficiency contributed to NSCL/P, we performed direct sequencing targeting all exons and exon-intron boundaries of MYCN in 104 multiplex families with mendelian NSCL/P and identified a novel pathogenic variant in MYCN. Taken together, our data indicate that ablation of Mycn in mouse CNCCs could resemble PRS by suppressing the Wnt5a-Sox9 signaling pathway in Merkel’s cartilage and that mutations in MYCN may be novel potential causes of NSCL/P.

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Novel IRF6 mutations in Chinese Han families with Van der Woude syndrome

Cited by 4 publications

References 30 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

Causal Variations at IRF6 Gene Identified in Van der Woude Syndrome Pedigrees

Mycndeficiency underlies the development of orofacial clefts in mice and humans

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