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. The latter are biphasic, including infantile dilated cardiomyopathy and distinct adult-onset cardiomyopathy, and poorly understood. We assesse...

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Bibliographic Details
Published in:Disease models & mechanisms 2024-06, Vol.17 (6)
Main Authors: McKay, Eleanor J, Luijten, Ineke, Broadway-Stringer, Sophie, Thomson, Adrian, Weng, Xiong, Gehmlich, Katya, Gray, Gillian A, Semple, Robert K
Format: Article
Language:English
Subjects:
alms1
alstrom syndrome
Alstrom Syndrome - complications
Alstrom Syndrome - genetics
alström syndrome
Animals
Cardiomyopathies - diagnostic imaging
Cardiomyopathies - genetics
Cardiomyopathies - pathology
Cardiomyopathies - physiopathology
cardiomyopathy
Cell Cycle Proteins - deficiency
Cell Cycle Proteins - genetics
ciliopathy
Echocardiography
Female
heart
Male
Mice
Mice, Knockout
Myocardium - metabolism
Myocardium - pathology
Myocytes, Cardiac - metabolism
Myocytes, Cardiac - pathology
Phenotype
primary cilia
Sex Characteristics
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Summary:Alström syndrome (AS), a multisystem disorder caused by biallelic ALMS1 mutations, features major early morbidity and mortality due to cardiac complications. The latter are biphasic, including infantile dilated cardiomyopathy and distinct adult-onset cardiomyopathy, and poorly understood. We assessed cardiac function of Alms1 knockout (KO) mice by echocardiography. Cardiac function was unaltered in Alms1 global KO mice of both sexes at postnatal day 15 (P15) and 8 weeks. At 23 weeks, female - but not male - KO 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 KO mice. Female mice with Pdgfra-Cre-driven Alms1 deletion in cardiac fibroblasts and in a small proportion of cardiomyocytes did not recapitulate the phenotype of global KO at 23 weeks. In conclusion, only female Alms1-deficient adult mice show echocardiographic evidence of cardiac dysfunction, consistent with the cardiomyopathy of AS. The explanation for sexual dimorphism remains unclear but might involve metabolic or endocrine differences between sexes.
ISSN:1754-8403
1754-8411
1754-8411
DOI:10.1242/dmm.050561