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This version published online on March 2, 2006
Molecular Endocrinology, doi:10.1210/me.2005-0494
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Submitted on December 7, 2005
Accepted on February 22, 2006

FAT AUSSIE - A NEW ALSTRÖM SYNDROME MOUSE SHOWING A CRITICAL ROLE FOR ALMS1 IN OBESITY, DIABETES AND SPERMATOGENESIS

Todor Arsov*, Diego G. Silva, Moira K. O'Bryan, Amanda Sainsbury, Nicola J. Lee, Claire Kennedy, Shehnaaz S.M. Manji, Keats Nelms, Conan Liu, Carola G. Vinuesa, David M. de Kretser, Christopher C. Goodnow, and Nikolai Petrovsky

John Curtin School of Medical Research, The Australian National University, Canberra ACT, Australia; The Canberra Hospital and The Australian National University Medical School, Canberra ACT, Australia; Monash Institute of Medical Research and The ARC Centre of Excellence in Biotechnology and Development, Monash University, Melbourne VIC, Australia; Garvan Institute of Medical Research, Sydney NSW, Australia; Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne VIC, Australia; Phenomix Aust Pty Ltd, Canberra ACT, Australia; The Australian Phenomics Facility, Canberra ACT, Australia; Flinders Medical Centre and Flinders University, Bedford Park, Adelaide SA, Australia

* To whom correspondence should be addressed. E-mail: todor.arsov{at}anu.edu.au.

Mutations in the human ALMS1 gene are responsible for Alström syndrome, a disorder in which key metabolic and endocrinological features include childhood onset obesity, metabolic syndrome and diabetes as well as infertility. ALMS1 localizes to the basal bodies of cilia and plays a role in intracellular trafficking, but the biological functions of ALMS1 and how these relate to the pathogenesis of obesity, diabetes and infertility remain unclear. Here we describe a new mouse model of Alström syndrome, fat aussie, caused by a spontaneous mutation in the Alms1 gene. Fat aussie (Alms1 foz/foz) mice are of normal weight when young but, by 120 days of age, they become obese and hyperinsulinemic. Diabetes develops in Alms1 foz/foz mice accompanied by pancreatic islet hyperplasia and islet cysts. Female mice are fertile before the onset of obesity and metabolic syndrome, however, male fat aussie mice are sterile due to a progressive germ cell loss followed by an almost complete block of development at the round to elongating spermatid stage of spermatogenesis. In conclusion, Alms1 foz/foz mouse is a new animal model in which to study the pathogenesis of the metabolic and fertility defects of Alström syndrome, including the role of ALMS1 in appetite regulation, pathogenesis of the metabolic syndrome, pancreatic islet physiology and spermatogenesis.
Key words: Alström syndrome • Alms1 • obesity • type 2 diabetes • sterility




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