In this study, we show that Alms1
-disrupted mice recapitulate many of the clinical features of the human syndrome. Obesity, hyperinsulinemia, hypogonadism, retinal degeneration and renal dysfunction parallel those observed in the human syndrome. Similar to individuals with AS, the onset of hyperinsulinemia in mice occurs early; whereas only males become hyperglycemic. Gender bias for Type 2 diabetes is typically observed in mouse models (20
). Pancreatic islets show marked hyperplasia associated with beta cell proliferation. This suggests that both insulin resistance and increased insulin secretion may contribute to the glucose intolerance observed.
When compared with the disease progression in human ALMS patients, some differences with respect to the onset and disease progression were observed in our mouse model. For instance, obesity is one of the earliest manifestations observed in human patients, usually presenting by the first year of life (1
). In contrast, prepubertal Alms1−/−
mice (4-week-old) tend to have lower body weights than their wild-type littermates, and the obesity manifests after puberty, between 8 and 12 weeks of age.
The deduced amino acid sequence of the ALMS1 protein has no similarity to other proteins with known function, nor does the protein sequence contain previously recognizable characterized domains. The first insight into ALMS1 function comes from the findings of Andersen et al.
) who identified ALMS1 as a constituent of centrosomes, microtubule organizing centers that assemble the mitotic spindle and organize the microtubule scaffold, which guides organelle and vesicle trafficking (21
). Additionally, in a recent study, ALMS1 was shown to localize to the basal bodies of ciliated cells as well as to the centrosomes (22
). Basal bodies anchor the microtubular axoneme of cilia and flagella and help organize intraflagellar transport (23
). In recent years, a role for these structures in human disease has become more evident (24
). Particularly, the proteins associated with diseases that are phenotypically similar to ALMS, such as BBS, also localize to the centrosomal regions and within the basal bodies of ciliated cells, and studies of mouse models for BBS (Bbs1−/−
) have implicated several BBS proteins in ciliary function and intracellular trafficking (12
Ultrastructural analyses of ciliated cells in Alms1−/−
mice reveal that cilia undergo normal assembly. However, disruption of the Alms1
gene in the retina results in the accumulation of large membrane-bound vesicles within photoreceptor inner segments and mislocalization of rhodopsin to the outer segments. Normally, rhodopsin-containing vesicles fuse with the cell membrane at the base of the connecting cilium of photoreceptor cells, and rhodopsin is transported to the photo-receptor outer segments along the cell membrane by an intraflagellar transport system (27
). The abnormal accumulation of vesicles in the photoreceptor inner segments in Alms1−/−
mice indicates a potential role of ALMS1 in ciliary function, perhaps in the process that brings rhodopsin vesicles to the base of the cilium, the docking of the vesicles to the membrane or the attachment of cargo to the intraflagellar transport machinery. A similar retinal phenotype is also observed in null mice deficient in the BBS4 protein, which has also been implicated in the formation and function of flagella (12
It is interesting to note that the retina of ALMS1−/−
mice closely resembles that of tubby and Tulp1−/−
mice whose outer segments form normal disc membranes, which eventually degenerate. In several retinal degeneration models including tubby and Tulp1−/−
mice, rhodopsin-containing vesicles accumulate in the inner segments (12
). Phenotypically, Alms1−/−
and tubby (tub
) mice are strikingly similar. Tubby mice exhibit adult-onset obesity and progressive retinal and cochlear degeneration. On specific genetic backgrounds, tubby mice become hyperinsulinemic and males are susceptible to Type 2 diabetes (32
). The similarities in clinical features lead us to speculate that ALMS1 and TUB proteins may function in similar biological pathways. Interestingly, the tubby superfamily protein has recently been identified in an analysis of the flagellar and basal body proteome (13
), and Tulp2
was found to be induced during flagellar regeneration in Chlamydomonas (33
), further suggesting a role for both TULPs and ALMS1 in cilia related functions.
In conclusion, the Alms1−/− mice described here recapitulate the phenotypes observed in patients with AS, including obesity, hyperinsulinemia leading to Type 2 diabetes, hypogonadism and neurosensory deficits. This new model for AS will allow detailed investigation of the disease pathology as well as testing hypotheses about ALMS1 function. Elucidation of the biochemical function of ALMS1 is crucial for a better understanding of the pathogenesis involved in AS as well as in the more common forms of obesity, diabetes and retinal and cochlear degeneration.