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Human Molecular Genetics Advance Access originally published online on July 6, 2005
Human Molecular Genetics 2005 14(16):2323-2333; doi:10.1093/hmg/ddi235
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org

Alms1-disrupted mice recapitulate human Alström syndrome

G.B. Collin1, E. Cyr1, R. Bronson1,2, J.D. Marshall1, E.J. Gifford1, W. Hicks1, S.A. Murray1, Q.Y. Zheng1,3, R.S. Smith1, P.M. Nishina1 and J.K. Naggert1,*

1The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA, 2Harvard Medical School, Boston, MA, USA and 3Department of Physiology, Key Laboratory of Environment and Genes Related Diseases, Xi'an Jiaotong University School of Medicine, Xi'an 710061, China

* To whom correspondence should be addressed. Tel: +1 2072886382; Fax: +1 2072886079; Email: jkn{at}jax.org

Received May 14, 2005; Revised June 15, 2005; Accepted June 28, 2005

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.


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