Modeling multisystemic nuclear envelopathies caused by LAP1 mutations using hPSCs

Mutations in human genes encoding essential protein components of the nuclear envelope (NE) are known to be associated with specific diseases collectively termed nuclear envelopathies. Although many of these NE proteins are ubiquitously expressed, most of the disease phenotypes are highly tissue-specific, with a particular emphasis on muscles and neuronal cells. A rare genetic disease caused by two different mutations in the TOR1AIP1 gene was recently identified. These mutations result in the combined loss of protein isoforms LAP1B and LAP1C from the inner nuclear membrane and lead to a severe, early onset multisystemic disease dominated by progressive neurological impairment, congenital heart malformations, growth retardation and early lethality.

Using patient derived iPSCs we explored the tissue specificity of this novel nuclear envelopathy. By the differentiation of the cells into neurons and cardiomyocytes we found a significant, but different, effect of the mutations on these two lineages. In the case of cardiomyocytes – the LAP1 mutations prevented the differentiation of the cells towards beating cardiomyocyte fibers. Moreover, we found a correlation between the effect of the two mutations on the in-vitro cardiomyocyte differentiation and their effect on heart development in the patients. By contrast, the LAP1 mutations did not prevent the differentiation of the cells towards neuronal lineage, but rather led to premature differentiation. This premature differentiation might explain the microcephaly phenotype of the patients.

Overall, our results demonstrate the utilization of patient-derived iPSCs as a tool to explore the tissue-specific effects of NE mutations in multisystemic disorders.