Alms1-disrupted mice recapitulate human Alström syndrome

G. B. Collin, E. Cyr, R. Bronson, J. D. Marshall, E. J. Gifford, W. Hicks, S. A. Murray, Q. Y. Zheng, R. S. Smith, P. M. Nishina, J. K. Naggert

Research output: Contribution to journalArticlepeer-review

150 Scopus citations

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 ∼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.

Original languageEnglish
Pages (from-to)2323-2333
Number of pages11
JournalHuman Molecular Genetics
Volume14
Issue number16
DOIs
StatePublished - 15 Aug 2005
Externally publishedYes

Fingerprint

Dive into the research topics of 'Alms1-disrupted mice recapitulate human Alström syndrome'. Together they form a unique fingerprint.

Cite this