Characterisation of a Missense Variant of the Alström Syndrome Centrosome and Basal Body Associated Protein (ALMS1) Gene Associated with Cardiomyopathy Using Induced Pluripotent Stem Cells.

BACKGROUND/

OBJECTIVES

Human induced pluripotent stem cell (hiPSC) models provide a unique platform for testing the effect of genomic variants identified in patients with inherited diseases. In Alström syndrome, a rare multisystem disorder mainly caused by nonsense mutations in the ALMS1 gene, patients often present with infantile cardiomyopathy, retinal dystrophy, type 2 diabetes, and hearing loss in addition to obesity. These diverse clinical manifestations highlight the pleiotropic functions of ALMS1 in cellular processes such as ciliary signalling, cell cycle regulation, and tissue homeostasis. In cats, the ALMS1:c.7384G>C missense variant has been associated with cardiomyopathy in the absence of other symptoms of Alström syndrome, raising questions regarding the impact of this variant on cardiac pathology.

METHODS

To answer these questions, we generated an hiPSC line carrying the human ALMS1:c.10004G>C missense variant, homologous to the ALMS1:c.7384G>C feline variant, as well as an isogenic control, to investigate the impact of this variant on cardiomyocyte differentiation and function.

RESULTS

The introduction of the ALMS1:c.10004G>C variant in the homozygous state in hiPSCs resulted in a significant reduction in cardiomyocyte differentiation efficiency. However, the variant did not affect contractile frequency, sarcomere organisation, sarcomere length, or cardiomyocyte cell size. Together, these results suggest that while the ALMS1:c.10004G>C variant impairs cardiomyocyte differentiation, it does not disrupt the structural or functional properties of the hiPSC-derived cardiomyocytes that do form.

CONCLUSIONS

We have generated and initiated the characterisation of the third ALMS1 mutant hiPSC line and the first line based on a missense variant, but further research is needed on its relevance in modelling ALMS1-related changes. Our results also support the previous recommendation not to use ALMS1:c.7384G>C for the selection of breeding cats until further data confirm its intrinsic pathogenicity.