Presentation: Mouse Model

Disease Research Report
Submitted by: Ellen Burns, Medical Liaison

Paper Presentation: Mouse Model for Hereditary Sensory Neuropathy Type I

Alex McCampbell, working in the Day Laboratory for Neuromuscular Research, presented a paper on hereditary sensory neuropathy in late 2004 at the Society for Neuroscience. Alex has been working for several years with Dr. Bob Brown, Jr., who is the Director of the Day Lab. Alex has been working to develop a strain of mice who demonstrate the defective gene found in the human form of HSN-1. Once referred to as the “Deater Disease,” HSN-1 is now known to be the most common hereditary disorder primarily affecting peripheral sensory neurons.

The gene with the mutations associated with HSN-1 is identified as SPTLC1. Genes make proteins; proteins make enzymes. SPTLC1 encodes one subunit of the serine palmitoyltransferase enzyme (SPT). This enzyme is known to affect the production of a fatty substance (glycosyl ceramide) in the body. Alex altered the genetic makeup of mice in several ways. He created transgenic mice. One group of mice have the mutated gene that is associated with HSN-1 added. The other group of mice was altered to over express the normal gene. The two groups were created to try to determine if the nerve damage in HSN-1 is caused by the SPT, which might mean SPT has a toxic, or poisonous effect, or if the damage might be caused by a decrease in the SPT activity, caused by the presence of the mutant protein.

Although mice and people share most of the same genetic structure, they are obviously not the same, and it is always uncertain if things are going to work the same way in mice as they do in people. For one thing, Alex had to find out if the mutant gene was reproduced when the mice reproduced. This was successful, and prepared the way for additional study. Then Alex had to determine if the genes added to the mice were functioning. The mice with the mutant gene did express the gene and did show significantly decreased activity of SPT. Some of the mice with the mutation were smaller than the normal mice.

The mice with the mutation showed decreased sensitivity to temperature sensation as they aged. The mice did not show any motor problems, or loss of function. However, because of the success of the development of the mice, it is thought that the mice may be a useful model of HSN-1. The researchers learned a lot from the development of the mice. More studies need to be done to take the research into HSN-1 further. The mice will be available for other researchers. Alex McCampbell has concluded his post-doctoral time with the Day Lab and has taken a job with Merck Laboratories; but Dr. Brown has hired a new technician to continue Alex’s work, which will also be pursued in the Day Laboratory by Dr. Florian Eichler, a pediatric neuropathologist on staff at the MGH and Harvard Medical School.