Human Molecular Genetics Advance Access originally published online on October 4, 2007
Human Molecular Genetics 2008 17(1):150-157; doi:10.1093/hmg/ddm291
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In vivo response to high-resolution variation of Tbx1 mRNA dosage
1 Institute of Biosciences and Technology, Texas A&M University Health Sciences Center, Houston, TX 77030, USA 2 Telethon Institute of Genetics and Medicine, University of Naples Federico II, Naples, Italy
* To whom correspondence should be addressed at: Telethon Institute of Genetics and Medicine (Tigem), Via Pietro Castellino 111, Napoli I-80131, Italy. Email: baldini{at}tigem.it; abaldini{at}ibt.tamhsc.edu
Received August 12, 2007; Accepted September 28, 2007
Mouse modeling of haploinsufficiency syndromes and, in general, of syndromes caused by gene dosage imbalance, is often unsatisfactory because loss (or gain) of one copy of the gene of interest is insufficient to recapitulate the disease phenotype. In this study, we use Tbx1 mutants, which model one of the most common haploinsufficiency disorders, the 22q11.2DS/DiGeorge/Velocardiofacial syndrome, to test the feasibility of high resolution dosage manipulation to generate mouse models that more closely resemble the human syndrome. We used nine different genotypes at the Tbx1 locus that are associated with progressively lower mRNA levels in vivo. We show that penetrance and expressivity of different phenotypic features became more severe as the dosage diminished, as expected, but the response was strikingly non-linear, with extreme examples such as neonatal lethality, which changed from 2 to 100% after a dosage reduction of just 
16%. Furthermore, heart phenotype variability, extreme in the human syndrome but very limited, or absent, in the standard knockout model, was seen when mRNA level was 20% of normal level, suggesting that there is a threshold level associated with unstable balance, which can be perturbed by chance events. Overall, our data suggest that there are developmental process-specific gene dosage thresholds beyond which the phenotype worsens very rapidly with very small mRNA level reductions.
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