Abstract
Hemochromatosis (iron storage disease) has been reported in diverse mammals including California sea lions (Zalophus californianus), bottlenose dolphins (Tursiops truncatus), northern fur seals (Callorhinus ursinus), and cattle.1-4 The primary cause of excessive iron storage in humans is hereditary hemochromatosis (HH). Most HH cases (> 80%) are caused by a point mutation in the HFE gene, resulting in a C282Y substitution.6 HFE signals hepatocyte transcription of hepcidin when serum iron concentrations are elevated. Hepcidin prevents iron within duodenal enterocytes from entering the blood stream, allowing removal from the body.5 The HFE C282Y mutation results in an inactive protein leading to iron accumulation.
Moderate to severe hepatic iron accumulation was histologically confirmed in liver biopsies of three adult Atlantic bottlenose dolphins (Tursiops truncatus) exhibiting chronic episodic elevations in ALT, AST, serum iron concentration, and serum transferrin saturation.2,3 Compared to healthy controls, these dolphins were more likely to have chronic hypercholesterolemia, chronic inflammation, and 2-hour postprandial hyperinsulinemia.2,7 No infectious etiology was indentified in any of these cases. To evaluate the possibility of an HH-like genetic predisposition in dolphins, we sequenced the bottlenose dolphin HFE gene from liver of affected dolphins as well as control dolphins. A blind study was conducted. RNA was extracted from each liver sample. Primers for dolphin HFE were designed from the dolphin genome. RT-PCR was performed and products were cloned before sequence and analysis.
While isotype diversity was evident, preliminary results show no coding differences in the HFE gene between any of the animals examined. Other genes associated with hemochromatosis/iron uptake will be examined to investigate potential genetic causes of hemochromatosis in Atlantic bottlenose dolphins. Given the presence of postprandial hyperinsulinemia among dolphins with hemochromatosis, another avenue for investigation is insulin resistance and type 2 diabetes, both of which can lead to high serum ferritin levels in people.8
Acknowledgements
This work was funded by research grants No. N00014-06-1-0250 and N00014-09-1-0252 from the Office of Naval Research to H.N and J.W. This project was supported by the Merck Merial Summer Research Program. The authors would like to thank Heather Daniel Maness, Dr. Rebecca Rivera, Kevin Carlin, and Risa Daniels for their assistance to this project.
References
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