Journal
HUMAN MOLECULAR GENETICS
Volume 14, Issue 16, Pages 2323-2333Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddi235
Keywords
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Funding
- NCI NIH HHS [CA24190] Funding Source: Medline
- NEI NIH HHS [EY14751, R24 EY014751, R24 EY014751-01] Funding Source: Medline
- NICHD NIH HHS [HD36878, R01 HD036878, R01 HD036878-09] Funding Source: Medline
- NIDCD NIH HHS [R01 DC004301-01, R01 DC004301, R01 DC005827, R01 DC005827-01, R21 DC005846-01A1, R21 DC005846, R03 DC004376-01A1] Funding Source: Medline
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Mutations in the human ALMS1 gene cause Alstrom 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 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.
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