Female Alms1-deficient mice develop echocardiographic features of adult but not infantile Alström Syndrome cardiomyopathy

Alström Syndrome (AS), a multisystem disorder caused by biallelic ALMS1 mutations, features major early morbidity and mortality due to cardiac complications. These are biphasic, including infantile dilated cardiomyopathy and distinct adult-onset cardiomyopathy, and are poorly understood. We assessed cardiac function of Alms1 knockout mice by echocardiography. Cardiac function was unaltered in global Alms1 knockout mice of both sexes at postnatal day 15 (P15) and 8 weeks. At 23 weeks, female, but not male knockout mice showed increased left atrial area and decreased isovolumic relaxation time, consistent with early restrictive cardiomyopathy, as well as reduced ejection fraction. No histological or transcriptional changes were seen in myocardium of 23-week-old female Alms1 global knockout mice. Female mice with Pdgfrα-Cre-driven Alms1 deletion in cardiac fibroblasts and a small proportion of cardiomyocytes did not recapitulate the phenotype of global knockout at 23 weeks. In conclusion, adult female, but not male, Alms1-deficient mice show echocardiographic evidence of cardiac dysfunction, consistent with the cardiomyopathy of AS. The explanation for sexual dimorphism remains unclear, but may involve metabolic or endocrine differences between sexes.