Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, UK.
Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, UK; Department of Cardiology, Queen Elizabeth Hospital, University Hospital Birmingham NHS Foundation Trust, Birmingham, Birmingham, UK.
Mol Genet Metab. 2024 Sep-Oct;143(1-2):108575. doi: 10.1016/j.ymgme.2024.108575. Epub 2024 Sep 2.
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 ALMS1 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 dynamics 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 β-galactosidase (SA-β gal) staining assay, we identified increased senescence of ALMS1 knockout iPSC-CMs. Overall, this study provides insights 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.
阿尔斯特伦综合征（AS）是一种遗传性罕见的纤毛病，其特征是多器官功能障碍和心血管疾病的早发。这可能表现为婴儿期起病的扩张型心肌病，伴有显著的相关死亡率。成人起病的限制型心肌病也可能在以后的生活中出现。ALMS1 中的功能丧失致病变异已在 AS 患者中被发现，导致 ALMS1 蛋白缺失。ALMS1 的生物学作用尚不清楚，尤其是在心血管方面。为了了解 ALMS1 在婴儿期心肌病中的作用，使用人类诱导多能干细胞衍生的心肌细胞（iPSC-CMs）对 AS 患者中观察到的 ALMS1 蛋白减少进行建模，其中 ALMS1 被敲除。肌肉运动分析和钙光学映射实验表明，与野生型（WT）相比，ALMS1 敲除（KO）细胞的收缩力增加，钙外排改变，钙处理动力学受损。 Seahorse 代谢测定表明，ALMS1 敲除 iPSC-CMs 的糖酵解和线粒体呼吸率增加，与 WT 相比，ALMS1 敲除细胞显示出更高的能量需求和呼吸能力。使用衰老相关β-半乳糖苷酶（SA-β gal）染色测定，我们鉴定出 ALMS1 敲除 iPSC-CMs 的衰老增加。总的来说，这项研究提供了对 AS 中分子机制的深入了解，特别是 ALMS1 在 AS 中婴儿期心肌病中的作用，使用 iPSC-CMs 作为“盘中疾病”模型，为这种复杂疾病的多个方面提供了深入了解。
