English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Zendy Open

Presents the pdf analysis as premium feature

PDF Analysis

Insights

Presents the summarisation as premium feature

Summarisation

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the zaia usage as premium feature

ZAIA

Zendy Tools

Zendy Plus

Presents the access of premium content as premium feature

Premium Content

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.

In vivo response to high-resolution variation of Tbx1 mRNA dosage