22q11 Deletion Syndrome: A Role for Tbx1 in Pharynx and Cardiovascular Development

Abstract

DiGeorge and velocardiofacial syndromes result from a chromosomal deletion involving proximal chromosome 22 and affected individuals commonly present with congenital heart defects, feeding problems, speech delay and learning problems. Psychiatric illness may present later in life. Mutation analysis and creation of mouse models which mimic the human disorder have identified that the Tbx1 (T‐box 1) transcription factor is the major dosage‐sensitive gene in the deletion region and have allowed exploration of the underlying developmental pathways and signalling networks disrupted in these syndromes. Of particular importance in this regard are Fgf (fibroblast growth factor) and retinoic acid signalling. Tbx1 is in genetic epistasis with loci encoding several transcription factors and signalling molecules, providing some rationale for the very variable clinical presentation. Gain‐of‐function, or duplications containing Tbx1, is also associated with heart defect.

Key Concepts:

  • The presence of a dominant phenotype secondary to gene hemizygosity is called haploinsufficiency.

  • Genetic epistasis is the phenomenon where the effects of one gene are modified by one or several other genes, which are called modifier genes.

  • Each pharyngeal arch surrounds an arch artery that connects the heart, by means of the aortic sac, to the dorsal aortae.

  • The neural crest is a pluripotent embryonic neuroectodermal cell population that migrates extensively and differentiates into diverse structures such as the face, neck, heart, adrenal gland, peripheral nervous system and skin.

  • Low copy number repeat are 1–400 kb blocks of genomic sequence that are duplicated in one or more locations on a chromosome and can act as substrates for aberrant recombination events.

Keywords: Tbx1; DiGeorge syndrome; velocardiofacial syndrome; conotruncal anomaly face syndrome

Figure 1.

Schematic comparing gene order in 22q11 with subcentromeric mouse chromosome 16. The arrows indicate the deletions of the Df1 mouse strain and typical human DiGeorge syndrome patient. Not all genes are represented, not all synonyms are used and physical distances are not to scale.

Figure 2.

The pharyngeal apparatus. (a) Side and frontal views of E10.5 Tbx1+/− embryo stained for LacZ. Tbx1 expressing domains are highlighted in blue and covered a large portion of the pharyngeal apparatus. (b) Schematic view of the pharyngeal apparatus at E10.5. It is composed of pharyngeal arches (PAs) and pouches. Each pharyngeal arch surrounds an arch artery (PAA) that connects the heart by means of the aortic sac, to the dorsal aortae. Tbx1 is expressed in the ectoderm, mesoderm and endoderm but not in the neural crest cell lineage of the pharyngeal apparatus. Ov. and dotted circle, otic vesicle. Adapted from Scambler , with permission from Springer.

Figure 3.

Tbx1 interaction summary. Tbx1 expression is negatively regulated by retinoic acid and Wnt‐β‐catenin signalling, and positively regulated by Shh and Chordin. Tbx1 has been shown to physically interact with both Srf and Smad1, which modulate its transcriptional activity. Expression and microarray studies have revealed a number of genes that have reduced expression in various tissues. Some of these genes (highlighted in different colours) interact with Tbx1, such that double heterozygote mouse embryos have a more severe/penetrant phenotype.

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How to Cite close
Calmont, Amelie, and Scambler, Peter(Sep 2010) 22q11 Deletion Syndrome: A Role for Tbx1 in Pharynx and Cardiovascular Development. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0006074.pub2]