Mutations in TBX1 genocopy the 22q11.2 deletion and duplication syndromes: a new susceptibility factor for mental retardation

Abstract

A screen for TBX1 gene mutations identified two mutations in patients with some features compatible with the 22q11.2-deletion syndrome but with no deletions. One is a de novo missense mutation and the other is a 5 0 untranslated region (5 0 UTR) C4T change that affects a nucleotide with a remarkable trans-species conservation. Computer modelling shows that the 5 0 UTR change is likely to affect the mRNA structure and in vitro translation experiments demonstrate that it produces a twofold increase in translation efficiency. Recently, duplications in the 22q11.2 region were reported in patients referred for fragile-X determination because of cognitive and behavioural problems. Because the 5 0 UTR nucleotide change may be a functional equivalent of a duplication of the TBX1 gene, we decided to screen 200 patients who had been referred for fragile-X determination and 400 healthy control individuals. As a result, we found the 5 0 UTR mutation to be present in three patients with mental retardation or behavioural problems and absent in control individuals of the same ethnic background. This observation suggests that it may be reasonable to screen for such mutation among patients with unspecific cognitive deficits and we provide an easy and quick way to do it with an amplification refractory mutation system (ARMS) approach. To our knowledge, this is the first human mutation showing that TBX1 is a candidate causing mental retardation associated with the 22q11.2 duplication syndrome.

β-catenin deficiency causes DiGeorge syndrome-like phenotypes through regulation of Tbx1

“…This suggests that the amount of TBX1 protein is crucial for normal development and that either loss or gain of TBX1 can cause DGS phenotypes. Consistent with a role in PA development, Tbx1 is expressed in the pharyngeal arch endoderm, core mesoderm, anterior heart field and head mesenchyme, but is absent in neural crest-derived mesenchyme (Chapman et al, 1996;Torres-Juan et al, 2007;Vitelli et al, 2002a).…”

“…Most cases of DGS are caused by deletion of chromosome 22q11.2, which includes the TBX1 gene. However, overexpression of human TBX1 in mice, or mutations that stabilize TBX1 in some DGS patients, also causes the same spectrum of DGS phenotypes (Torres-Juan et al, 2007;Zweier et al, 2007). This indicates that the level of expression of Tbx1 is crucial for PA formation.…”

“…Transgenic mice which have an additional human TBX1 gene and patients which have a mutation that stabilizes the TBX1 protein also develop DGS phenotypes (Liao et al, 2004;Torres-Juan et al, 2007;Zweier et al, 2007). This suggests that the amount of TBX1 protein is crucial for normal development and that either loss or gain of TBX1 can cause DGS phenotypes.…”

Tbx1 Genetically Interacts With the Transforming Growth Factor-β/Bone Morphogenetic Protein Inhibitor Smad7 During Great Vessel Remodeling

“…This phenotype has been associated with lack of TBX1 in DiGeorge syndrome patients [9][10][11]42,43 and animal models. 12,13 Despite this, to date only 2 genes have been described as directly regulated by Tbx1.…”

Genetic counseling for the 22q11.2 deletion

“…Of note, mice that are haploinsufficient for TBX1 have several features which have been seen in humans with homologous deletions, in particular, structural cardiac anomalies [Baldini, 2005]. Recently, patients with normal 22q11.2 deletion studies using the commercially available FISH probes (N25 or TUPLE) but with overlapping clinical features of the deletion, have been reported with both gain and loss of function mutations in TBX1 [Yagi et al, 2003;Torres-Juan et al, 2007;Zweir et al, 2007], as well as, atypical or unique 22q11.2 deletions, some of which include TBX1 and others which do not [Kurahashi et al, 1996;O'Donnell et al, 1997;Yamagishi et al, 1998;Amati et al, 1999;McQuaide et al, 1999;Shaikh et al, 2000;GarciaMinaur et al, 2002;McDonald-McGinn et al, 2008]. Nonetheless, with the exception of congenital heart disease and its association with TBX1, to date, there have been no clear genotype-phenotype correlations in the remainder of the patients [McDonald-McGinn et al, 2001b, 2008.…”