Alms1-disrupted mice recapitulate human Alström syndrome

Abstract

Mutations in the human ALMS1 gene cause Alström syndrome (AS), a progressive disease characterized by neurosensory deficits and by metabolic defects including childhood obesity, hyperinsulinemia and Type 2 diabetes. Other features that are more variable in expressivity include dilated cardiomyopathy, hypertriglyceridemia, hypercholesterolemia, scoliosis, developmental delay and pulmonary and urological dysfunctions. ALMS1 encodes a ubiquitously expressed protein of unknown function. To obtain an animal model in which the etiology of the observed pathologies could be further studied, we generated a mouse model using an Alms1 gene-trapped ES cell line. Alms1-/- mice develop features similar to patients with AS, including obesity, hypogonadism, hyperinsulinemia, retinal dysfunction and late-onset hearing loss. Insulin resistance and increased body weight are apparent between 8 and 12 weeks of age, with hyperglycemia manifesting at approximately 16 weeks of age. In addition, Alms1-/- mice have normal hearing until 8 months of age, after which they display abnormal auditory brainstem responses. Diminished cone ERG b-wave response is observed early, followed by the degeneration of photoreceptor cells. Electron microscopy revealed accumulation of intracellular vesicles in the inner segments of photoreceptors, whereas immunohistochemical analysis showed mislocalization of rhodopsin to the outer nuclear layer. These findings suggest that ALMS1 has a role in intracellular trafficking.

Decreased body weight and hepatic steatosis with altered fatty acid ethanolamide metabolism in aged L-Fabp mice

“…In our search to explain how deletion of the same gene could produce a nearly opposite phenotype in two different laboratories, we surveyed expression of genes near the Fabp1 locus and surrounding obesity-related QTLs, including some genes ( Alms1, Retstat, Aqp1 ) that have been implicated in metabolic adaptations and body weight maintenance (28)(29)(30)(31)(32)(33). No evidence was found for gene duplication or altered expression of modifi er genes in this region in our L-Fabp Ϫ / Ϫ mice.…”

Systematic identification of personal tumor-specific neoantigens in chronic lymphocytic leukemia

“…Deconvolution of the pool revealed that the mutated (mut) ALMS1 and C6ORF89 peptides within pool 2 were immunogenic ( Figure 4C). ALMS1 plays a role in ciliary function, cellular quiescence, and intracellular transport, 37,38 whereas C6ORF89 encodes a protein that interacts with bombesin receptor subtype 3 (involved in cell cycle progression and wound repair of bronchial epithelial cells).…”

Mechanistic insights into Bardet-Biedl syndrome, a model ciliopathy

“…Bbs1-4, Bbs6-8, Bbs9, and Bbs11 are all expressed during mouse adipogenesis (76), suggesting they may play a role in the generation of fat tissue. 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).…”