Abstract
Genetic causes of obesity include the ciliopathies Alström syndrome and Bardet–Biedl syndrome. In these disorders, mutations cause dysfunction of the primary cilium, an organelle involved in intracellular and intercellular sensing and signaling. Alström syndrome is an autosomal-recessive disorder caused solely by mutations in ALMS1. By contrast, Bardet–Biedl syndrome is caused by mutations in at least 14 genes involved in primary cilium function. Despite equivalent levels of obesity, patients with Alström syndrome are more likely than those with Bardet–Biedl syndrome to develop childhood type 2 diabetes mellitus (T2DM), suggesting that ALMS1 might have a specific role in β-cell function and/or peripheral insulin signaling pathways. How mutations in genes that encode proteins involved in primary cilium function lead to the clinical phenotypes of these syndromes is being revealed by work in mutant mouse models. With the aid of these models, insights are being obtained into the pathogenic mechanisms that underlie obesity, insulin resistance and T2DM. Research into ciliopathies, including Alström syndrome and Bardet–Biedl syndrome, should lead not only to improved treatments for individuals with these genetic disorders, but also to improved understanding of the cellular pathways involved in other common causes of obesity and T2DM.
Key Points
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The ciliopathies are caused by dysfunction of the primary cilium, which results in altered intracellular and intercellular sensing and signaling
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Alström syndrome is a rare ciliopathy caused by mutations in ALMS1
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Symptoms of Alström syndrome include childhood obesity, type 2 diabetes mellitus (T2DM), retinal degeneration, sensorineural deafness, cardiomyopathy, hepatic dysfunction, renal impairment and infertility
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As obesity and T2DM are associated with several ciliopathies, the primary cilium could be involved in appetite control, adipose tissue regulation, insulin signaling and β-cell function
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Research into ciliopathies could cast new light on endocrine signaling pathways, which might lead to the development of novel treatments for patients with obesity and T2DM
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Change history
17 December 2010
In the version of this article initially published online, there was an error in the name of a receptor. 5-hydroxytryptamine receptor 3 (5HT3) should have read somatostatin receptor 3 (SSTR3). The error has been corrected in all electronic versions of the text.
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Acknowledgements
The authors acknowledge the financial support of the Canberra Hospital Private Practice Fund towards the initial characterization studies of the fat aussie Alström syndrome mutant strain. D. Girard is the recipient of a PhD scholarship from Flinders University and Vaxine Pty Ltd.
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Girard, D., Petrovsky, N. Alström syndrome: insights into the pathogenesis of metabolic disorders. Nat Rev Endocrinol 7, 77–88 (2011). https://doi.org/10.1038/nrendo.2010.210
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