Full spectrum of malformations in velo-cardio-facial syndrome/DiGeorge syndrome mouse models by altering Tbx1 dosage

Abstract

Velo-cardio-facial syndrome/DiGeorge syndrome (VCFS/DGS) is associated with de novo hemizygous 22q11.2 deletions and is characterized by malformations attributed to abnormal development of the pharyngeal arches and pouches. The main physical findings include aortic arch and outflow tract heart defects, thymus gland hypoplasia or aplasia and craniofacial anomalies. The disorder varies greatly in expressivity; while some patients are mildly affected with learning disabilities and subtle craniofacial malformations, others die soon after birth with major cardiovascular defects and thymus gland aplasia. In addition to the main clinical features, many other findings are associated with the disorder such as chronic otitis media and hypocalcemia. Tbx1, a gene encoding a T-box transcription factor, which is hemizygously deleted on chromosome 22q11.2, was found to be a strong candidate for the equivalent of human VCFS/DGS in mice. Mice hemizygous for a null allele of Tbx1 had mild malformations, while homozygotes had severe malformations in the affected structures; neither precisely modeling the syndrome. Interestingly, bacterial artificial chromosome (BAC) transgenic mice overexpressing human TBX1 and three other transgenes, had similar malformations as VCFS/DGS patients. By employing genetic complementation studies, we demonstrate that altered TBX1 dosage and not overexpression of the other transgenes is responsible for most of the defects in the BAC transgenic mice. Furthermore, the full spectrum of VCFS/DGS malformations was elicited in a Tbx1 dose dependent manner, thus providing a molecular basis for the pathogenesis and varied expressivity of the syndrome.

Variable phenotype in 17q12 microdeletions: Clinical and molecular characterization of a new case

“…This hypothesis is compatible with what is already documented in some microdeletion syndromes, for example in 22q11.2 (Xu et al, 2013) and with what has been observed in cases of 17q12 duplication, where over-expression of miR-2909 could cause the decrease of the levels of FOXP2 expression: in fact several studies described deletions of this gene as responsible for language and cognitive disorders. It is widely accepted that, deletion and duplication of dose sensitive genes, as in 22q11 deletions/duplication, may cause a similar phenotype: mice over-and underexpressing TBX1 result in phenotypes similar to that of velocardiofacial syndrome (VCFS) (Liao et al, 2004). Thus we suggest that FOXP2 could be characterized by a similar mechanism, and therefore speech delay and cognitive impairment observed in our patient may be caused by miR-2909 deletion.…”

Microduplications of 22q11.2 are frequently inherited and are associated with variable phenotypes

“…46 -49 Interestingly, it has been observed in mouse models that both over-and under-expression of TBX1 recapitulates the DGS/ VCFS phenotype. 50,51 Recently, gain of function mutations in TBX1 have been reported patients with overlapping phenotypes with DGS/VCFS. 49,52 The above studies suggest that TBX1 dosage outside of normal range may affect the same developmental pathways in humans and contribute to the DGS/ VCFS and the 22q11.2 duplication syndrome.…”

Expression of Islet1 in thyroid development related to budding, migration, and fusion of primordia

“…Consequently, deletion of any of these genes results in aplasia or severe dysgenesis of the gland (Kimura, 1996;De Felice et al, 1998;Mansouri et al, 1998;Martinez Barbera et al, 2000). Transcription factors regulating pharyngeal arch development, e.g., Hox (Manley and Capecchi, 1998), Eya1 (Xu et al, 2002), and Tbx1 (Liao et al, 2004) contribute also to the formation and maturation of the ultimobranchial bodies. Interestingly, Nkx2.1 is the only transcription factor so far known to be expressed in both the thyroid diverticulum and the ultimobranchial bodies (Mansouri et al, 1998), suggesting that mechanisms governing their development might in part follow similar regulatory pathways.…”