Characterisation of infantile cardiomyopathy in Alström Syndrome using ALMS1 Knockout induced pluripotent stem cell derived cardiomyocyte model

Alström syndrome (AS) is an inherited rare ciliopathy characterised by multi -organ dysfunction and premature cardiovascular disease. This may manifest as an infantile -onset dilated cardiomyopathy with significant associated mortality. An adult - onset restrictive cardiomyopathy may also feature later in life. Loss of function pathogenic variants in ALMS 1 have been identified in AS patients, leading to a lack of ALMS1 protein. The biological role of ALMS1 is unknown, particularly in a cardiovascular context. To understand the role of ALMS1 in infantile cardiomyopathy, the reduction of ALMS1 protein seen in AS patients was modelled using human induced pluripotent stem cell -derived cardiomyocytes (iPSC -CMs), in which ALMS1 was knocked out. MuscleMotion analysis and calcium optical mapping experiments suggest that ALMS1 knockout (KO) cells have increased contractility, with altered calcium extrusion and impaired calcium handling dynamic s compared to wildtype (WT) counterparts. Seahorse metabolic assays showed ALMS1 knockout iPSC -CMs had increased glycolytic and mitochondrial respiration rates, with ALMS1 knockout cells portraying increased energetic demand and respiratory capacity than WT counterparts. Using senescence associated -galactosidase (SA - gal) staining assay, we identified increased senescence of ALMS1 knockout iPSC -CMs. Overall, this study provides insight s into the molecular mechanisms in AS, particularly the role of ALMS1 in infantile cardiomyopathy in AS, using iPSC -CMs as a ‘disease in a dish’ model to provide insights into multiple aspects of this complex disease.