A Role for Alström Syndrome Protein, Alms1, in Kidney Ciliogenesis and Cellular Quiescence

Abstract

Premature truncation alleles in the ALMS1 gene are a frequent cause of human Alström syndrome. Alström syndrome is a rare disorder characterized by early obesity and sensory impairment, symptoms shared with other genetic diseases affecting proteins of the primary cilium. ALMS1 localizes to centrosomes and ciliary basal bodies, but truncation mutations in Alms1/ALMS1 do not preclude formation of cilia. Here, we show that in vitro knockdown of Alms1 in mice causes stunted cilia on kidney epithelial cells and prevents these cells from increasing calcium influx in response to mechanical stimuli. The stunted-cilium phenotype can be rescued with a 5′ fragment of the Alms1 cDNA, which resembles disease-associated alleles. In a mouse model of Alström syndrome, Alms1 protein can be stably expressed from the mutant allele and is required for cilia formation in primary cells. Aged mice developed specific loss of cilia from the kidney proximal tubules, which is associated with foci of apoptosis or proliferation. As renal failure is a common cause of mortality in Alström syndrome patients, we conclude that this disease should be considered as a further example of the class of renal ciliopathies: wild-type or mutant alleles of the Alström syndrome gene can support normal kidney ciliogenesis in vitro and in vivo, but mutant alleles are associated with age-dependent loss of kidney primary cilia.

Current status on genome–metabolome-wide associations: an opportunity in nutrition research

“…We suspect that the greater genetic diversity of our study population has resulted in a breakdown of the linkage disequilibrium in the ALMS1/NAT8 region of the genome, which resulted in a sharper association peak. While the molecular function of ALMS1 is not known, genetic variations within ALMS1 have been implicated in a number of kidney health disorder phenotypes (Chambers et al 2010) including a rare genetic disease called Alström syndrome (Li et al 2007). We further confirmed the association (Nicholson et al 2011) observed for trimethylamine (TMA), thus confirming the strong impact of genetics on the metabolism of a precursor to the major cardiovascular risk factor TMAO (Wang et al 2011).…”

Polycystin-dependent fluid flow sensing targets histone deacetylase 5 to prevent the development of renal cysts

“…S3 in the supplementary material). The duration of the calcium peaks was in the range of 10-20 seconds, similar to that from single-cell measurements in a recent study using Fura-2 calcium sensor in Dolichos biflorus agglutinin (DBA)-positive mouse embryonic kidney (MEK) cells (Li et al, 2007). Using this experimental setup, we performed an expression microarray analysis to identify genes whose expression levels were altered in response to fluid flow in a PC1-dependent manner.…”

Mechanistic insights into Bardet-Biedl syndrome, a model ciliopathy

“…Other ciliary proteins have also been implicated in this process, including retinitis-pigmentosa GTPase regulator interacting protein 1-like (RPGRIP1L), which localizes to the basal body (77) and whose expression is decreased in the adipose tissue of mutants for the adjacent FTO gene (78) and the Alström syndrome gene ALMS1, for which obese knockout mice have been generated (79,80). The ALMS1 protein, which localizes to the basal body (81,82), is expressed in the early phases of adipogenesis and may be involved in the conversion of preadipocytes to adipocytes (83). It remains to be determined whether hypothalamic dysfunction alone is sufficient to induce obesity in BBS and other ciliopathies.…”