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Human Molecular Genetics Advance Access published online on July 6, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi235
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received May 14, 2005
Revised June 15, 2005
Accepted June 28, 2005

Article

Alms1-disrupted mice recapitulate human Alström syndrome

G. B. Collin 1, E. Cyr 1, R. Bronson 2, J. D. Marshall 1, E. J. Gifford 1, W. Hicks 1, S. A. Murray 1, Q. Y. Zheng 3, R. S. Smith 1, P. M. Nishina 1, and J. K. Naggert 1*

1 The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine 04609, USA
2 The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine 04609, USA; Harvard Medical School, Boston, Massachusetts, USA
3 The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine 04609, USA; Department 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.
J. K. Naggert, E-mail: jkn{at}jax.org


  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 dysfunction. 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. Alms 1-/- mice develop similar features to patients with AS including obesity, hypogonadism, hyperinsulinemia, retinal dysfunction and late-onset hearing loss. Insulin resistance and increased body weight are apparent between eight and twelve weeks of age, with hyperglycemia manifesting at ~16 weeks of age. Also, Alms1-/- mice have normal hearing until eight months of age, after which they display abnormal auditory brainstem responses. Diminished cone ERG b-wave response is observed early, followed by degeneration of photoreceptor cells. Electron microscopy revealed accumulation of intracellular vesicles in the inner segments of photoreceptors while immunohistochemical analysis showed mislocalization of rhodopsin to the outer nuclear layer. These findings suggest ALMS1 has a role in intracellular trafficking.


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