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Alms1-disrupted mice recapitulate human

By Q. Y. Zheng, R. S. Smith, P. M. Nishina and J. K. Naggert

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, hypertrigly-ceridemia, hypercholesterolemia, scoliosis, developmental delay and pulmonary and urological dysfunc-tions. 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. Alms12/2 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 hyperglyce-mia manifesting at16 weeks of age. In addition, Alms12/2 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 accumu-lation of intracellular vesicles in the inner segments of photoreceptors, whereas immunohistochemical analy-sis showed mislocalization of rhodopsin to the outer nuclear layer. These findings suggest that ALMS1 has a role in intracellular trafficking

Topics: Alström syndrome (AS) [ALMS, Online Mendelian Inheri
Year: 2005
OAI identifier: oai:CiteSeerX.psu:10.1.1.548.4549
Provided by: CiteSeerX
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