Preprint proposes splicing-modulation strategy to model haploinsufficiency disorders in mice

A preprint posted on bioRxiv presents a generalised approach to modelling haploinsufficiency — conditions caused by a heterozygous loss-of-function variant that reduces gene product to roughly half normal levels — in preclinical animal models. Heterozygous loss-of-function variants underlie a wide range of human genetic disorders, but conventional heterozygous mouse knockouts frequently fail to reproduce human disease phenotypes, thought to be in part because post-translational compensation mechanisms restore near-normal protein levels.

The framework uses genome editing to introduce hypomorphic splice-altering alleles that redirect a defined proportion of transcripts towards nonsense-mediated decay (NMD), a cellular quality-control pathway that degrades aberrant mRNAs before they can be translated. By combining multiple such alleles, the researchers were able to titrate functional protein output to levels intended to overwhelm compensatory mechanisms. The approach was applied to Mybpc3, the gene encoding cardiac myosin-binding protein C, variants in which are among the most common causes of hypertrophic cardiomyopathy.

The authors describe the framework as generalisable in principle to other haploinsufficiency disorders. The method may be of interest to researchers developing disease models for rare genetic conditions and to those studying the relationship between gene dosage, protein homeostasis, and phenotypic penetrance. This is a preprint and has not yet been peer-reviewed.