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Alms1-disrupted mice recapitulate human Alström syndrome.

Human molecular genetics | Aug 15, 2005

http://www.ncbi.nlm.nih.gov/pubmed/16000322

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 approximately 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.

Pubmed ID: 16000322 RIS Download

Mesh terms: Animals | Diabetes Mellitus, Type 2 | Disease Models, Animal | Electroretinography | Female | Hearing Loss | Humans | Hyperinsulinism | Insulin Resistance | Male | Mice | Mice, Inbred C57BL | Mice, Knockout | Nerve Degeneration | Obesity | Protein Transport | Proteins | Retinal Degeneration | Sequence Homology, Amino Acid | Syndrome

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Associated grants

  • Agency: NCI NIH HHS, Id: CA24190
  • Agency: NEI NIH HHS, Id: EY14751
  • Agency: NICHD NIH HHS, Id: HD36878
  • Agency: NIDCD NIH HHS, Id: R01 DC004301
  • Agency: NIDCD NIH HHS, Id: R01 DC004301-01
  • Agency: NIDCD NIH HHS, Id: R01 DC005827
  • Agency: NIDCD NIH HHS, Id: R01 DC005827-01
  • Agency: NICHD NIH HHS, Id: R01 HD036878
  • Agency: NICHD NIH HHS, Id: R01 HD036878-09
  • Agency: NIDCD NIH HHS, Id: R03 DC004376
  • Agency: NIDCD NIH HHS, Id: R03 DC004376-01A1
  • Agency: NIDCD NIH HHS, Id: R21 DC005846
  • Agency: NIDCD NIH HHS, Id: R21 DC005846-01A1
  • Agency: NEI NIH HHS, Id: R24 EY014751-01

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