The TFAP2A–IRF6–GRHL3 genetic pathway is conserved in neurulation

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Mutations in IRF6 , TFAP2A and GRHL3 cause orofacial clefting syndromes in humans. However, Tfap2a and Grhl3 are also required for neurulation in mice. Here, we found that homeostasis of Irf6 is also required for development of the neural tube and associated structures. Over-expression of Irf6 caused exencephaly, a rostral neural tube defect, through suppression of Tfap2a and Grhl3 expression. Conversely, loss of Irf6 function caused a curly tail and coincided with a reduction of Tfap2a and Grhl3 expression in tail tissues. To test whether Irf6 function in neurulation was conserved, we sequenced samples obtained from human cases of spina bifida and anencephaly. We found two likely disease-causing variants in two samples from patients with spina bifida. Overall, these data suggest that the Tfap2a-Irf6-Grhl3 genetic pathway is shared by two embryologically distinct morphogenetic events that previously were considered independent during mammalian development. In addition, these data suggest new candidates to delineate the genetic architecture of neural tube defects and new therapeutic targets to prevent this common birth defect.

Related collections

Most cited references 52

Record: found
Abstract: found
Article: not found

Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes.

Shinji Kondo, Brian Schutte, Rebecca Richardson … (2002)

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-alpha and -beta after viral infection, 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 pits, 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 anomalies. Phenotypic overlap and linkage data 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.

0 comments Cited 176 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

The genetic basis of mammalian neurulation.

Nicholas Greene, Jennifer Murdoch, Andrew J. Copp (2003)

More than 80 mutant mouse genes disrupt neurulation and allow an in-depth analysis of the underlying developmental mechanisms. Although many of the genetic mutants have been studied in only rudimentary detail, several molecular pathways can already be identified as crucial for normal neurulation. These include the planar cell-polarity pathway, which is required for the initiation of neural tube closure, and the sonic hedgehog signalling pathway that regulates neural plate bending. Mutant mice also offer an opportunity to unravel the mechanisms by which folic acid prevents neural tube defects, and to develop new therapies for folate-resistant defects.

0 comments Cited 146 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Interferon regulatory factor 6 (IRF6) gene variants and the risk of isolated cleft lip or palate.

Eduardo Castilla, Ann Cooper, Maggie B. Maher … (2004)

Cleft lip or palate (or the two in combination) is a common birth defect that results from a mixture of genetic and environmental factors. We searched for a specific genetic factor contributing to this complex trait by examining large numbers of affected patients and families and evaluating a specific candidate gene. We identified the gene that encodes interferon regulatory factor 6 (IRF6) as a candidate gene on the basis of its involvement in an autosomal dominant form of cleft lip and palate, Van der Woude's syndrome. A single-nucleotide polymorphism in this gene results in either a valine or an isoleucine at amino acid position 274 (V274I). We carried out transmission-disequilibrium testing for V274I in 8003 individual subjects in 1968 families derived from 10 populations with ancestry in Asia, Europe, and South America, haplotype and linkage analyses, and case-control analyses, and determined the risk of cleft lip or palate that is associated with genetic variation in IRF6. Strong evidence of overtransmission of the valine (V) allele was found in the entire population data set (P<10(-9)); moreover, the results for some individual populations from South America and Asia were highly significant. Variation at IRF6 was responsible for 12 percent of the genetic contribution to cleft lip or palate and tripled the risk of recurrence in families that had already had one affected child. DNA-sequence variants associated with IRF6 are major contributors to cleft lip, with or without cleft palate. The contribution of variants in single genes to cleft lip or palate is an important consideration in genetic counseling. Copyright 2004 Massachusetts Medical Society

0 comments Cited 108 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Journal

Title: Human Molecular Genetics

Publisher: Oxford University Press (OUP)

ISSN (Print): 0964-6906

ISSN (Electronic): 1460-2083

Publication date Created: May 15 2019

Publication date Created: January 25 2019

Publication date Other: May 15 2019

Publication date (Print): May 15 2019

Publication date (Electronic): January 25 2019

Volume: 28

Issue: 10

Pages: 1726-1737

Affiliations

[1 ]Departments of Biochemistry and Molecular Biology

[2 ]Division of Neurology, Childrens National Health System

[3 ]Center for Neuroscience Research, The Childrens Research Institute, Washington, DC, USA

[4 ]Dell Pediatric Research Institute, Department of Nutritional Sciences, University of Texas at Austin, Austin, TX, USA

[5 ]Department of Diagnostic & Biomedical Sciences, School of Dentistry, University of Texas Health Science Center at Houston, Houston, TX, USA

[6 ]Department of Human Genetics, Nagasaki University, Nagasaki, Japan

[7 ]Microbiology and Molecular Genetics

[8 ]Human Genetics Center, Division of Epidemiology, Human Genetics and Environmental Sciences, University of Texas School of Public Health, Houston, TX, USA

[9 ]Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA

[10 ]Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA

[11 ]Departments of Pediatrics

[12 ]Genetics PhD Program

[13 ]Department of Clinical Pathology, School of Medicine, University of Mansoura, Mansoura, Egypt

[14 ]Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, CA, USA

[15 ]Anatomy and Cell Biology, University of Iowa, Iowa City, IA, USA

[16 ]Center for Regenerative Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

[17 ]Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA

[18 ]Center for Statistical Training & Consulting, Michigan State University, East Lansing, MI, USA

[19 ]Department of Craniofacial Biology, University of Colorado Denver at Anschutz Medical Campus, Aurora, CO, USA

[20 ]Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, Los Angeles, CA, USA

[21 ]Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, USA

[22 ]Pediatrics and Human Development

Article

DOI: 10.1093/hmg/ddz010

PMC ID: 6494790

PubMed ID: 30689861

SO-VID: 455aaf1e-b5ce-430f-9e1b-2f6026cd5d8d

History

Data availability:

Comments

Comment on this article

scite_

Cited by 10

See all cited by

- Version 1

The TFAP2A–IRF6–GRHL3 genetic pathway is conserved in neurulation

Read this article at

Abstract

Related collections

ScienceOpen Research

Most cited references 52

Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes.

The genetic basis of mammalian neurulation.

Interferon regulatory factor 6 (IRF6) gene variants and the risk of isolated cleft lip or palate.

Author and article information

Journal

Affiliations

Article

History

Comments

Comment on this article

Similar content 2,925

Cited by 10