Differential expression of the IRF6 gene in the signs of Van der Woude Syndrome: Are distinct genetic modifiers operating?

Rosany de Oliveira Lisboa, Cláudia Maria da Rocha Martins, Maria Elisabete Silva Santos, Danilo Leôncio Aguiar Pereira, Flávia Martinez de Carvalho, Ieda Maria Orioli, João Farias Guerreiro, Alexandre Rezende Vieira, Luiz Carlos Santana-da-Silva

Abstract


Objective: The purpose of this study was to report a new variant in the Interferon Regulatory Factor 6 gene (IRF6) and to determine phenotype-genotype correlations in a family segregating Van der Woude syndrome.

Methods: A five-generation family of 80 individuals segregating VWS was investigated using a tabulated pedigree but considering that three individuals registered in the pedigree died shortly after birth, the final sample size was 77 individuals.  Five individuals had a complete dental clinical examination and molecular analysis performed using direct sequencing of the exon 4 and an adjacent region with 23 base pairs of the IRF6 gene.

Results: Features of VWS reported in family history were present in 36.4% (28/77) of all family members; of these 57% (16/28) had pits in the lower lip, 36% (10/28) had both pits and orofacial clefts and 7 % (2/28) had only orofacial clefts. Developmental dental anomalies were observed in three individuals. The sequence analysis of exon 4 of the IRF6 gene carried out for 4 family members revealed the presence of the SNP rs7552506 (c.175-5C> G) located in five base pairs before the start of exon. The analysis of exon 4 of the IRF6 gene also revealed a new variant c.269G>C (p.Ser90Thr) which causes exchange of the Serine amino acid residue for the Threonine residue.

 Conclusions: The c.269G>C(p.Ser90Thr) can interfere with multimeric interactions and with protein conformation that will be slightly destabilized, because the mutant residue is bigger than the wild-type residue. The phenotypic variations in the cases studied, despite carrying the same genetic mutation, suggest that distinct genetic modifiers operate on the formation of clefts and dental development.


Keywords


Van der Woude syndrome; Orofacial clefts; IRF6 gene

Full Text:

PDF

References


Cleft lip - a comprehensive review. Shkoukani MA, Chen M, Vong A. Front Pediatr. 2013 Dec. 53 (1): 1 - 10. PMID: 2440029.

Van der Woude syndrome: clinical presentation in 64 patients. Huang JJ, Hou JW, Tan YC, Chen KT, Lo LJ, Chen YR. Cleft Palate Craniofac J. 2007 Nov;44(6):649-52. PMID: 18177185.

Van der Woude syndrome: a review of 11 cases seen at the Lagos University Teaching Hospital. James O, Adeyemo WL, Emeka CI, Ogunlewe MO, Ladeinde AL, Butali A. Afr J Paediatr Surg. 2014 Jan-Mar;11(1):52-5. PMID: 24647295.

Van der Woude syndrome: a review. Cardinal signs, epidemiology, associated features, differential diagnosis, expressivity, genetic counselling and treatment. Rizos M, Spyropoulos MN. Eur J Orthod. 2004 Feb;26(1):17-24. PMID: 14994878.

The penetrance and variable expression of the Van der Woude syndrome: implications for genetic counseling. Shprintzen RJ, Goldberg RB, Sidoti EJ. Cleft Palate J. 1980 Jan;17(1):52-7. PMID: 6928118.

Epidemiology of Van der Woude syndrome from mutational analyses in affected patients from Pakistan. Malik S, Kakar N, Hasnain S, Ahmad J, Wilcox ER, Naz S. Clin Genet. 2010 Sep;78(3):247-56. PMID: 20184620.

Van der Woude syndrome: dentofacial features and implications for clinical practice. Lam AK, David DJ, Townsend GC, Anderson PJ. Aust Dent J. 2010 Mar;55(1):51-8. PMID: 20415912.

Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes. Kondo S, Schutte BC, Richardson RJ, Bjork BC, Knight AS, Watanabe Y, Howard E, de Lima RL, Daack-Hirsch S, Sander A, McDonald-McGinn DM, Zackai EH, Lammer EJ, Aylsworth AS, Ardinger HH, Lidral AC, Pober BR, Moreno L, Arcos-Burgos M, Valencia C, Houdayer C, Bahuau M, Moretti-Ferreira D, Richieri-Costa A, Dixon MJ, Murray JC. Nat Genet. 2002 Oct;32(2):285-9. PMID: 12219090.

An etiologic regulatory mutation in IRF6 with loss- and gain-of-function effects. Fakhouri WD, Rahimov F, Attanasio C, Kouwenhoven EN, Ferreira De Lima RL, Felix TM, Nitschke L, Huver D, Barrons J, Kousa YA, Leslie E, Pennacchio LA, Van Bokhoven H, Visel A, Zhou H, Murray JC, Schutte BC. Hum Mol Genet. 2014 May 15;23(10):2711-20. PMID: 24442519.

Dominant mutations in GRHL3 cause Van der Woude Syndrome and disrupt oral periderm development. Peyrard-Janvid M, Leslie EJ, Kousa YA, Smith TL, Dunnwald M, Magnusson M, Lentz BA, Unneberg P, Fransson I, Koillinen HK, Rautio J, Pegelow M, Karsten A, Basel-Vanagaite L, Gordon W, Andersen B, Svensson T, Murray JC, Cornell RA, Kere J, Schutte BC. Am J Hum Genet. 2014 Jan 2;94(1):23-32. PMID: 24360809.

A preliminary gene map for the Van der Woude syndrome critical region derived from 900 kb of genomic sequence at 1q32-q41. Schutte BC, Bjork BC, Coppage KB, Malik MI, Gregory SG, Scott DJ, Brentzell LM, Watanabe Y, Dixon MJ, Murray JC. Genome Res. 2000 Jan;10(1):81-94. PMID: 10645953.

The IRF family of transcription factors: Inception, impact and implications in oncogenesis. Yanai H, Negishi H, Taniguchi T. Oncoimmunology. 2012 Nov 1;1(8):1376-1386. PMID: 23243601.

Maternal Interferon Regulatory Factor 6 is required for the differentiation of primary superficial epithelia in Danio and Xenopus embryos. Sabel JL, d'Alençon C, O'Brien EK, Van Otterloo E, Lutz K, Cuykendall TN, Schutte BC, Houston DW, Cornell RA. Dev Biol. 2009 Jan 1;325(1):249-62. PMID: 19013452.

Abnormal skin, limb and craniofacial morphogenesis in mice deficient for interferon regulatory factor 6 (Irf6). Ingraham CR, Kinoshita A, Kondo S, Yang B, Sajan S, Trout KJ, Malik MI, Dunnwald M, Goudy SL, Lovett M, Murray JC, Schutte BC. Nat Genet. 2006 Nov;38(11):1335-40. PMID: 17041601.

IRF family of transcription factors as regulators of host defense. Taniguchi T, Ogasawara K, Takaoka A, Tanaka N. Annu Rev Immunol. 2001;19: 623-55. PMID: 11244049.

Interferon Regulatory Factor 6 Is Necessary for Salivary Glands and Pancreas Development. Metwalli KA, Do MA, Nguyen K, Mallick S, Kin K, Farokhnia N, Jun G, Fakhouri WD. J Dent Res. 2018 Feb;97(2):226-236. PMID: 28898113.

Genealogical data in population medical genetics: Field guidelines.Poletta FA, Orioli IM, Castilla EE. Genet Mol Biol. 2014 Mar;37(1 Suppl):171-85. PMID: 24764752.

Protein structure analysis of mutations causing inheritable diseases. An e-Science approach with life scientist friendly interfaces. Venselaar H, Te Beek TA, Kuipers RK, Hekkelman ML, Vriend G. BMC Bioinformatics. 2010 Nov 8;11:548. PMID: 21059217.

PROVEAN web server: a tool to predict the functional effect of amino acid substitutions and indels. Choi Y, Chan AP. Bioinformatics. 2015 Aug 15;31(16):2745-7. PMID: 25851949.

SIFT web server: predicting effects of amino acid substitutions on proteins. Sim NL, Kumar P, Hu J, Henikoff S, Schneider G, Ng PC. Nucleic Acids Res. 2012 Jul;40(Web Server issue):W452-7. PMID: 22689647.

Predicting functional effect of human missense mutations using PolyPhen-2. Adzhubei I, Jordan DM, Sunyaev SR. Curr Protoc Hum Genet. 2013 Jan; Chapter 7:Unit7.20. PMID: 23315928.

Novel IRF6 mutations in families with Van Der Woude syndrome and popliteal pterygium syndrome from sub-Saharan Africa. Butali A, Mossey PA, Adeyemo WL, Eshete MA, Gaines LA, Even D, Braimah RO, Aregbesola BS, Rigdon JV, Emeka CI, James O, Ogunlewe MO, Ladeinde AL, Abate F, Hailu T, Mohammed I, Gravem PE, Deribew M, Gesses M, Adeyemo AA, Murray JC. Mol Genet Genomic Med. 2014 May;2(3):254-60. PMID: 24936515.

Clinical and genetic features of Van der Woude syndrome in two large families in Brazil. Martelli-Junior H, Chaves MR, Swerts MS, de Miranda RT, Bonan PR, Coletta RD. Cleft Palate Craniofac J. 2007 May;44(3):239-43. PMID: 17477759.

Congenital Symmetrical Lower Lip Pits: Van der Woude Syndrome. Ibrahim A, Ajike S. Oman Med J. 2015 Jan;30(1):e081. PMID: 30838101.

Wound complications after cleft repair in children with Van der Woude syndrome. Jones JL, Canady JW, Brookes JT, Wehby GL, L'Heureux J, Schutte BC, Murray JC, Dunnwald M. J Craniofac Surg. 2010 Sep;21(5):1350-3. PMID: 20856020.

The genetics of isolated orofacial clefts: from genotypes to subphenotypes. Jugessur A, Farlie PG, Kilpatrick N. Oral Dis. 2009 Oct;15(7):437-53. PMID: 19583827.

Gene/environment causes of cleft lip and/or palate. Murray JC. Clin Genet. 2002 Apr;61(4):248-56. PMID: 12030886.

Identification of IRF6 gene variants in three families with Van der Woude syndrome. Tan EC, Lim EC, Yap SH, Lee ST, Cheng J, Por YC, Yeow V. Int J Mol Med. 2008 Jun;21(6):747-51. PMID: 18506368.

Prevalence and nonrandom distribution of exonic mutations in interferon regulatory factor 6 in 307 families with Van der Woude syndrome and 37 families with popliteal pterygium syndrome. de Lima RL, Hoper SA, Ghassibe M, Cooper ME, Rorick NK, Kondo S, Katz L, Marazita ML, Compton J, Bale S, Hehr U, Dixon MJ, Daack-Hirsch S, Boute O, Bayet B, Revencu N, Verellen-Dumoulin C, Vikkula M, Richieri-Costa A, Moretti-Ferreira D, Murray JC, Schutte BC. Genet Med. 2009 Apr;11(4):241-7. PMID: 19282774.

Familial non-syndromic cleft lip and palate--analysis of the IRF6 gene and clinical phenotypes. Pegelow M, Peyrard-Janvid M, Zucchelli M, Fransson I, Larson O, Kere J, Larsson C, Karsten A. Eur J Orthod. 2008 Apr;30(2):169-75. PMID: 18209213.

Novel mutations in the IRF6 gene for Van der Woude syndrome. Wang X, Liu J, Zhang H, Xiao M, Li J, Yang C, Lin X, Wu Z, Hu L, Kong X. Hum Genet. 2003 Oct;113(5):382-6. PMID: 12920575.

Van der woude syndrome with short review of the literature. Deshmukh PK, Deshmukh K, Mangalgi A, Patil S, Hugar D, Kodangal SF. Case Rep Dent. 2014; 2014:871460. PMID: 25050184.

Hypoplasia and hypodontia in Van der Woude syndrome. Oberoi S, Vargervik K. Cleft Palate Craniofac J. 2005 Sep;42(5):459-66. PMID: 16149825.

Dental agenesis: genetic and clinical perspectives. De Coster PJ, Marks LA, Martens LC, Huysseune A. J Oral Pathol Med. 2009 Jan;38(1):1-17. PMID: 18771513.




DOI: https://doi.org/10.5195/d3000.2021.164



Copyright (c) 2021 Rosany de Oliveira Lisboa, Cláudia Maria da Rocha Martins, Maria Elisabete Silva Santos, Danilo Leôncio Aguiar Pereira, Flávia Martinez de Carvalho, Ieda Maria Orioli, João Farias Guerreiro, Alexandre Rezende Vieira, Luiz Carlos Santana-da-Silva

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.