22q11.2 Deletion Syndrome: Unmasking the Role of Tbx1 in Craniofacial Development

Review Article

Austin Med Sci. 2016; 1(1): 1001.

22q11.2 Deletion Syndrome: Unmasking the Role of Tbx1 in Craniofacial Development

Funato N*

Human Gene Sciences Center, Tokyo Medical and Dental University, Japan

*Corresponding author: Funato N, Research Center for Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan

Received: December 18, 2015; Accepted: January 19, 2016; Published: January 21, 2016


T-box transcription factor gene (TBX1) is thought to be responsible for chromosome 22q11.2 deletion syndrome (DiGeorge/velocardiofacial syndrome), which is characterized by craniofacial defects, cardiac malformations, thymic and parathyroid hypoplasia, and cleft palates. TBX1 regulates the cell fate of progenitor cells in cranial and pharyngeal tissues during embryogenesis. In this review, I discuss the mechanisms of TBX1 during craniofacial development of tissues including the palate, bones, teeth, and muscle.

Keywords: DiGeorge syndrome; Velocardiofacial syndrome; Pharyngeal arch; Palatogenesis; Bone anomalies; Cleidocranial dysplasia


22q11.2DS: 22q11.2 deletion syndrome; CP: cleft palate; SNP: single nucleotide polymorphism; CCD: cleidocranial dysplasia; CL: cervical loop; FGF: fibroblast growth factor


TBX1, a member of the T-box transcription factor gene family, is considered to be a candidate gene for chromosome 22q11.2 deletion syndrome (22q11.2DS). 22q11.2DSmanifests as DiGeorge syndrome (OMIM 188400), velocardiofacial syndrome (OMIM 192430), and conotruncal anomaly face syndrome (OMIM 217095).22q11.2DS is the most frequent micro-deletion syndrome, affecting approximately 1 in 4000 live births, and is characterized by a series of phenotypic abnormalities, including craniofacial anomalies, cardiovascular defects, thymic and parathyroid hypoplasia, velopharyngeal insufficiency, and skeletal muscle hypotonia [1-4]. Structures primarily affected in 22q11.2DS are derivatives of the pharyngeal arches and head mesenchyme [4,5].

TBX1 is expressed in the pharyngeal tissues, including mesoderm, ectoderm, and endoderm, and throughout the head mesenchyme in mice [6-8] (Figure 1A). TBX1knockout (Tbx1–/–) mice exhibit most features of 22q11.2DS, including cardiac, craniofacial, thymic, and parathyroid defects, and skeletal muscle hypotonia [1-3,8,9]. Craniofacial anomalies occur in ~60% of 22q11.2DS patients [5]; the most frequent craniofacial defects include micrognathia, ear abnormalities, hypertelorism, blunted nose, various degrees of Cleft Palate (CP), and tooth defects [5,10,11]. This review focuses on the functions of TBX1incraniofacial development.

Tbx1 and cleft palate

CP is the most frequent craniofacial birth defects in humans, occurring in 1 in 500 to 1000 live births worldwide [6]. The craniofacial malformations observed in 22q11DS patients include various subtypes of CP (complete CP, incomplete CP, sub mucosal CP, and bifid uvula). TBX1 mutations have been identified in patients with characteristic phenotypes of 22q11.2DS, conotruncal anomaly face syndrome (OMIM 217095), and nonsyndromic CP [12,13]. These findings suggest that TBX1 is a potential candidate gene for various degrees of nonsyndromic CP. Indeed, two adjacent Single Nucleotide Polymorphisms (SNPs) upstream of TBX1 suggest a potential association with the CP phenotype, although they are not significant after correcting for multiple testing [14]. Regulatory elements for TBX1 expression on 22q11.2 may also be involved in the CP phenotype.

TBX1 is expressed in both the anterior and posterior edges of the paired palatal shelves in mice, highlighting the intrinsic function of TBX1 in regulating palatogenesis. Deletion of TBX1 results in abnormal epithelial fusion between the palatal shelves and the mandible, which induces CP by inhibiting elevation of the palatal shelves [15]. Tbx1–/– mice present various degrees of CP phenotype, including complete CP, incomplete CP, submucosal CP, and anterior CP, whereas Tbx1+/–mice are phenotypically normal [15] (Table 1). Ablation of TBX1 specifically in the epithelial cells (TBX1LoxP/KO; KRT14-Cre) results in anterior CP [15]. The variations in palatal phenotypes across different TBX1 mutants strongly suggest that TBX1 is involved in stochastic factors and/or modifier genes. Expression of Pax9, mutations of which lead to CP and adontogenesis [16], is down-regulated in the pharyngeal arch and palatal shelves of Tbx1- /- embryos [15,17]. Tbx1–/– hyperproliferative epithelium displays incomplete differentiation, suggesting that TBX1 controls the balance between proliferation and differentiation of epithelial cells. CP phenotypes of Tbx1–/– mice suggest that the various degrees of CP phenotypes could be induced by the pathogenic adhesion-separation of the oral epithelium, together with compromised growth of palatal mesenchyme [15,18].

Citation: Funato N. 22q11.2 Deletion Syndrome: Unmasking the Role of Tbx1 in Craniofacial Development. Austin Med Sci. 2016; 1(1): 1001.