International Journal of Pediatric Otorhinolaryngology 78 (2014) 1579–1585 Contents lists available at ScienceDirect International Journal of Pediatric Otorhinolaryngology journal homepage: www.elsevier.com/locate/ijporl Review Article Role of angiogenesis-related genes in cleft lip/palate: Review of the literature C. Franc¸ois-Fiquet a,b,c,*, M.L. Poli-Merol a, P. Nguyen b, E. Landais d, D. Gaillard d, M. Doco-Fenzy b,d a Department of Pediatric Surgery, American Memorial Hospital, CHU Reims, France b EA 3801 Laboratory Champagne Ardenne University, SFR CAP sante´ Reims-Amiens, Reims, France c Department of Plastic and Reconstructive Surgery, Hopital Maison Blanche, CHU Reims, France d Genetics Department, Hoˆpital Maison Blanche, CHU Reims, France ARTICLE INFO ABSTRACT Article history: Objectives: Cleft lip and cleft palate (CLP) are the most common congenital craniofacial anomalies. They Received 24 May 2014 have a multifactorial etiology and result from an incomplete fusion of the facial buds. Two main Received in revised form 30 July 2014 mechanisms,acting alone orinteracting with each other, were evidenced inthisfusion defect responsible for Accepted 1 August 2014 CLP: defective tissue development and/or defective apoptosis in normal or defective tissues. The objective of Available online 12 August 2014 this work was to study the implication and role of angiogenesis-related genes in the etiology of CL/P. Methods: Our methodological approach included a systematic and thorough analysis of the genes Keywords: involved in CL/P (syndromic and non-syndromic forms) including previously identified genes but also Cleft lip genes that could potentially be angiogenesis-related (OMIM, Pub Med).We studied the interactions of Cleft palate Gene these different genes and their relationships with potential environmental factors. Genetic Results: TGFb, FGA, PDGFc, PDGFRa, FGF, FGFR1, FGFR2 growth factors as well as MMP and TIMP2 Angiogenesis proteolytic enzymes are involved in the genesis of CLP (P>L). Furthermore, 18 genes involved in CLP also Etiologic interact with angiogenesis-related genes. Discussion: Even if the main angiogenesis-related genes involved in CLP formation are genes participating in several biological activities and their implication might not be always related to angiogenesis defects, they nevertheless remain an undeniably important research pathway. Furthermore, their interactions with environmental factors make them good candidates in the field of CLP prevention. ß 2014 Elsevier Ireland Ltd. All rights reserved. Contents 1. Introduction . 1580 2. Materials and methods . 1580 3. Results (Tables 1 and 2).......................................................................................... 1581 4. Discussion . 1581 4.1. TGF pathways . 1581 4.1.1. TGFA. 1581 4.1.2. TGFb ............................................................................................ 1582 4.2. PDGFC and PDGFRa. 1583 4.3. FGF and FGFR . 1583 4.4. VEGF.................................................................................................... 1583 4.5. Proteolytic enzymes: MMP and TIMP2 . 1584 5. Conclusion . 1584 Acknowledgements . 1584 References . 1584 * Corresponding author at: Department of Pediatric surgery, American Memorial Hospital, 47 rue Cognacq Jay, 51092 Reims, France. Tel.: +33 682873893; fax: +33 326784318; mobile: +33 06 82 87 38 93. E-mail addresses: [email protected], carolinefi[email protected] (C. Franc¸ois-Fiquet). http://dx.doi.org/10.1016/j.ijporl.2014.08.001 0165-5876/ß 2014 Elsevier Ireland Ltd. All rights reserved. 1580 C. Franc¸ois-Fiquet et al. / International Journal of Pediatric Otorhinolaryngology 78 (2014) 1579–1585 1. Introduction - Significant increase of this gene abnormality compared to the general population Clefts of the lip-palate (CLP) are age-old and multi-ethnic - Existence of functional studies on these genes pertaining to CL/P pathologies. They are the most common congenital craniofacial (gene expression studies or animal models studies) deformities, resulting from incomplete fusion of the facial buds at The search yielded 1118 relevant articles [17/07/2013]. the beginning of pregnancy. In spite of their frequency and age-old For each gene: nature, the etiology of this pathology has only been partially We collected the following general data: explained to this day. However, it has been recognized that several factors are involved. Genetic and environmental factors as well as OMIM reference their interactions have been implied in CLP etiology. Mechanisms Gene localization that could potentially explain this incomplete fusion of the facial buds Its size are quite complex. Two main mechanisms, acting independently or in Its role, its function (when it was clearly identified) association, have been identified: tissue development defect and/or apoptosis defect that can act on normal or defective tissues. Then we analyzed the implication of these genes in CL/P based The term angiogenesis was used for the first time in 1935 by on: Hertig to describe the growth of blood vessels within the placenta. Folkman used the term again in 1972 to describe a neovascular- Analysis of the type of cleft (CL, CP, CL/P) correlated to this gene ization associated with solid tumor growth. Nowadays, angiogen- Analysis of the syndromic or non-syndromic type esis has been correlated to several mechanisms during Analysis of the type of genetic abnormalities highlighted (e.g. embryogenesis and postnatal periods. mutation, deletion, polymorphism) and/or genetic techniques The objective of this work was to investigate the role of used angiogenesis-related genes in the study of CLP etiology. A search for potential interactions with other genes or signaling pathways 2. Materials and methods A search for an interaction with the environment, as well as the agent responsible (e.g. tobacco, alcohol, toxic agent, vitamin Our research was conducted on several databases and the two deficit) main ones were: A search for family studies or maternal studies described A search for animal models described - OMIM (Online Mendelian Inheritance in Man): with the Analysis of the implication of this gene in CL/P, while following keywords ‘‘Cleft, Cleft lip, Cleft palate, Cleft lip palate, underlining the possibility that the implication of this gene might lip, palate’’. We unveiled 331 OMIM references for the item ‘‘cleft be uncertain or its role indirect. lip, cleft palate’’, including 314 corresponding really to CL/P. And finally, we collected references on the gene in relation with - PubMed: with the following keywords ‘‘Cleft, Cleft lip, Cleft CL/P. palate, Cleft lip palate, gene, genetics, mutation’’. A first selection based on the abstracts led to discarding articles Thanks to the data collected on the genes function, we selected that did not focus on cleft lip or cleft palate, when an article did in from all the genes (potentials or involved) those who had an fact underline genetics and cleft lip/palate it was selected and read impact on the angiogenic mechanisms. in its entirety. The genes we considered relevant had to meet one or We also focused on the interactions and signaling pathways. more of the following criteria: Thus, we looked for the following interactions: - Description in the article of a deleterious genetic abnormality - Between the angiogenic genes. Meaning, angiogenic genes (underlining a mutation or deleterious gene rearrangement in a involved in CL/P and other angiogenic genes not known for patient). their involvement in CL/P. - Recurrence in several articles of the same observation or the - Between an angiogenic gene linked to CL/P and other genes not same subject related to the angiogenesis but linked to CL/P. Table 1 Overview of relevant genes in CL/P genesis. Gene Phenotype Genetic Gene or pathway Environmental Familial or Animal interaction interaction maternal study study Cleft Non-syndromic Syndromic FGF8 CL/P Cleft and Polymorphism variants, SHH Mouse hypogonadotropic mutation (de novo hypogonadism missense mutation) FGF 9 CP (animal), CLP Gene–gene interaction test FGF18 X FGFR1 x Kallmann Mutation, Deletion X FGFR2 CL/P Apert, crouzon Deletion X MMP3 CL+/-P X Polymorphism variants, TIMP2? gene–gene interaction test PDGF-C CP, CL+/-P x Linkage X Mouse PDGFRa CP x Mutation PAX1 X X Mouse, zebrafish TGFA CL Æ P x Polymorphism, linkage, X X Mouse mutation TGFB3 CP X Polymorphism X X Dog, mouse TIMP2 CL Æ P x Polymorphism MMP3 VEGF CP Di george TBX1 Rats, rabbits C. Franc¸ois-Fiquet et al. / International Journal of Pediatric Otorhinolaryngology 78 (2014) 1579–1585 1581 Table 2 Role and function of relevant genes in CL/P genesis. Gene Name Localization OMIM Size (bp) Role/function FGF8 FIBROBLAST GROWTH FACTOR 8; FGF8 10q24.32 600483 5.941 Fibroblast growth factors are secreted proteins that ANDROGEN-INDUCED GROWTH FACTOR; interact with FGF tyrosine kinase receptors to AIGF mediate growth and development. The temporal and spatial patterns of FGF8 gene expression suggest that FGF8 is involved in gastrulation, regionalization of the brain, and organogenesis of the limb and face as an embryonic epithelial factor FGF 9 FIBROBLAST GROWTH FACTOR 9 13q12.11 600921 33.426 Peptide regulatory factors that act through distinct tyrosine kinase receptors and are involved in various biologic processes during embryogenesis and adult life, including implantation, morphogenesis, angiogenesis, and possibly tumorigenesis FGFR1 FIBROBLAST GROWTH FACTOR RECEPTOR 1; 8p11.23-p11.22 136350 57.697 Role in regulating cellular responses elicited