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Cleft palate: players, pathways, and pursuits
Jeffrey C. Murray and Brian C. Schutte
Department of Pediatrics and Craniofacial Anomalies Research Center, University of Iowa, Iowa City, Iowa, USA.
Address correspondence to: Jeffrey C. Murray, Department of Pediatrics and Craniofacial Anomalies Research Center, 2182 MedLabs, University of Iowa, Iowa City 52242, Iowa, USA. Phone: (319) 335-6897; Fax: (319) 335-6970; E-mail: jeff-murray@uiowa.edu.
Find articles by Murray, J. in: JCI | PubMed | Google Scholar
Department of Pediatrics and Craniofacial Anomalies Research Center, University of Iowa, Iowa City, Iowa, USA.
Address correspondence to: Jeffrey C. Murray, Department of Pediatrics and Craniofacial Anomalies Research Center, 2182 MedLabs, University of Iowa, Iowa City 52242, Iowa, USA. Phone: (319) 335-6897; Fax: (319) 335-6970; E-mail: jeff-murray@uiowa.edu.
Find articles by Schutte, B. in: JCI | PubMed | Google Scholar
Published June 15, 2004 - More info
J Clin Invest. 2004;113(12):1676–1678. https://doi.org/10.1172/JCI22154.
© 2004 The American Society for Clinical Investigation
Human birth defects arise from many etiologies, including single-gene disorders, chromosome aberrations, exposure to teratogens, and sporadic conditions of unknown cause. Birth defect syndromes include multiple structural abnormalities and/or cognitive delays. However, most human birth defects affect a single organ system, and those disrupting facial structures are found in approximately 1% (or 1 million) of infants born worldwide each year. The most common of these birth defects is cleft lip and/or palate, a complex trait caused by multiple genetic and environmental factors (1).
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Genes that play a role in palate development
As shown in Figure 1, the secondary palate develops as an outgrowth of the maxillary prominences at about embryonic day (E) 11.5 in the mouse. The palate shelves initially grow vertically down the side of the tongue (E12.5) and then elevate above the tongue as it drops in the oral cavity (E13.5). With continued growth, the shelves appose in the midline (E14.5) and fuse (E15.5). Growth of the palate shelves depends on the survival and continued proliferation of mesenchymal cells that originate from neural crest and mesodermal cells of the first pharyngeal arch. In this issue of the JCI, using transgenic animal models Rice and coworkers provide details of the interactions between the epithelium and mesenchyme that lead to palate growth and development (2). They demonstrate a signaling process in which Fgf10 is expressed in the mesenchyme, then activates its receptor, FGF receptor 2b (Fgfr2b), which is located in the epithelium. Finally, Fgfr2b mediates expression of sonic hedgehog (Shh) in the epithelium.
Figure 1Signaling molecules essential for palate development. (A) Transverse section of embryonic palate. (B) Schematic of sections of normal palate shelf (ps; blue) development at the indicated days after conception. Palate shelves emanate from maxillary prominences (E11.5), grow, and extend vertically past the tongue (E12.5). The tongue (T; pink) drops, allowing the palate shelves to elevate (E13.5), appose (E14.5), and fuse (E15.5). (C and D) Cell-specific expression of signaling molecules during palate growth (C) and fusion (D). Genes involved in palate growth may also be involved in fusion. The γ-aminobutyric acid receptor subunit β3 (Gabrb3) is also involved in palate elevation (not shown). Molecules are expressed in the epithelium (yellow) or mesenchyme (blue). Molecules shown to be essential for palate development are indicated for mouse (oval), human (underlined), and both mouse and human (rectangle). Arrows indicate known (black) or predicted (gray) gene-gene (straight) and gene-environment (wavy) interactions. Ahr, aryl-hydrocarbon receptor; Alk5, activin receptor_like kinase 5; Bmp4, bone morphogenic protein 4; Bzd’s, benzodiazepines; Msx1, msh-like 1 homeo box; Ptc, patched homolog 1; Pvrl1, poliovirus receptor_related 1; SATB2, SATB family member 2; TBX22, T-box 22; Tgfb3, transforming growth factor β3.
Additional genetic factors involved in palate development have been described using mouse transgenic models; in particular, mice lacking the muscle segment–specific homeobox Msx1 (3) or the signaling molecule Tgfb3 (4) exhibit cleft palate. While many other gene knockouts also result in palate or other craniofacial defects, in most cases the gene deletions and/or insertions cause multiple structural or functional defects. Consequently, evaluation of the role of a particular gene in palate formation has not been possible. The function of Msx1 and Tgfb3 in palate development was extended to isolated forms of clefting in humans. Point mutations and/or statistical analyses have indicated a role for these factors in cases of cleft lip and/or palate in which the only other feature was dental abnormalities (1, 5). In parallel with the advances made from the study of animal models, complementary progress has been made to identify additional genes that play a direct role in human palate development.
Two recent gene discovery reports are particularly relevant to human palate development. In the first, mutations were identified in the gene that encodes the transcription factor interferon regulatory factor 6 (IRF6), resulting in the autosomal dominant disorder Van der Woude syndrome (VWS) (6). VWS is an especially important model for isolated cleft lip and palate. In the clinic, the only difference between individuals with VWS and those with isolated cleft lip and palate is the presence of pits in the lower lip of most VWS cases. In addition, VWS is caused by mutations in a single gene, whereas the more common isolated cleft is a complex trait caused by multiple gene mutations and/or environmental insults. Very recently it was demonstrated that a common haplotype associated with IRF6 contains a mutation that provides an attributable risk of approximately 12% to all common forms of cleft lip and palate (7). In a second report, nonsense mutations and deletions in the FGFR1 gene were identified in cases of Kallmann syndrome (8), an autosomal dominant disorder typically characterized by infertility and anosmia. However, approximately 5% of Kallmann syndrome cases have clefts of the lip and/or palate and, as with VWS, some individuals may present with clefts as the only component of the phenotype. Other genes that play a role in human palate development were reviewed recently (P63, PVRL1, TGFA, and TBX22; ref 1) or were reported (SATB2) (9).
One remarkable feature of the genes IRF6, MSX1, and FGFR1 is that mutations in any of the three are associated with dental anomalies and “mixed clefting.” Mixed clefting refers to disorders in which cases of isolated cleft palate and cleft lip (with or without cleft palate) occur in the same pedigree. Clefts of the lip or clefts of the lip with the palate arise in the primary palate, whereas clefts of the palate alone occur in the secondary palate. Mixed clefting disorders suggest that identical mechanisms cause these two forms, which previously had been separated based on embryologic and genetic evidence (1). The presence of dental anomalies in some individuals who have mutations in each of these three genes suggests that these same pathways are common to tooth development.
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