Alstrom syndrome: insights into the pathogenesis of metabolic disorders

Genetic causes of obesity include the ciliopathies Alstrom 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. Alstrom 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 Alstrom 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 beta-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 Alstrom 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.