Genetics and signaling mechanisms of orofacial clefts

Abstract

Craniofacial development involves several complex tissue movements including several fusion processes to form the frontonasal and maxillary structures, including the upper lip and palate. Each of these movements are controlled by many different factors that are tightly regulated by several integral morphogenetic signaling pathways. Subject to both genetic and environmental influences, interruption at nearly any stage can disrupt lip, nasal, or palate fusion and result in a cleft. Here, we discuss many of the genetic risk factors that may contribute to the presentation of orofacial clefts in patients, and several of the key signaling pathways and underlying cellular mechanisms that control lip and palate formation, as identified primarily through investigating equivalent processes in animal models, are examined.

Role of epigenetics and miRNAs in orofacial clefts

“…They also demonstrated that miR‐17‐92 was regulated by Bmp signaling and its expression was directly controlled by Ap‐2α. This is consistent with previous findings linking deficient BMP signaling to OFCs in both humans and mice (Liu et al, 2005; S. Suzuki et al, 2009; Reynolds et al, 2020, in this issue). These results demonstrated two key points for craniofacial development: (a) Bmp signaling may be transduced through Smad factors and miRNA‐17‐92; and (b) miR‐17‐92 may exhibit multiplicity of action by targeting several pathways, including Tgfβ, Fgf, Wnt, and others.…”

“…Environmental factors can also influence histone modifications—TCDD exposure, for example, alters the acetylation of H3 during murine palatogenesis (Cuiping et al, 2014). Since histone‐modifying enzymes can alter chromatin at several loci, mutations affecting their function often result in syndromes including those that exhibit OFCs (Reynolds et al, 2020, in this issue). Here we briefly summarize some mechanistic studies providing evidence for the role of histone modifiers in OFCs.…”

“…As detailed in a companion review (Ji et al, 2020, in this issue), elongation and elevation of the palatal shelves during craniofacial development involves epithelial to mesenchymal transition (EMT) and other processes including apoptosis. These are under the control of several crucial morphogenetic signaling pathways (Reynolds et al, 2020, in this issue), including Tgfβ signaling. In mice, miR‐200b expression was detected in the palatal mesenchyme and medial edge epithelium prior to shelf fusion, and in the midline epithelial seam during fusion (Shin et al, 2012).…”

Folate intake, markers of folate status and oral clefts: An updated set of systematic reviews and meta‐analyses

“…Folates are essential vitamins needed for amino acid production and many other cellular development processes and insufficient intake might cause OFCs. One of the most studied genes involved in nsCLP, MTHFR , encodes the folate metabolism enzyme methylenetetrahydrofolate reductase (Reynolds et al, 2020). The enzyme converts 5,10‐methylenetetrahydrofolate to 5‐methyltetrahydrofolate, the primary form of folate found in blood, and involved in the DNA and methylation cycles (World Health Organization, 2002). The two most common variants of the MTHFR gene are located at nucleotides 677 (C677T) and 1,298 (A1298C).…”

Environmental mechanisms of orofacial clefts

“…Orofacial cleft (OFC) is among the most common birth defects affecting newborns and occurs at an average frequency of 1 out of 700 live births. Craniofacial structures are formed within the first 10 weeks of human development, involving a tight coordination between molecular signaling pathways (Reynolds et al, 2020; in this issue) and cellular processes such as proliferation, migration, differentiation, transition, and apoptosis (Ji et al, 2020; in this issue). Perturbation of any of these processes could offset the delicate balance required for normal craniofacial morphogenesis and results in birth defects such as OFCs.…”