Mutant SPTLC1

Mutant SPTLC1 dominantly inhibits serine palmitoyltransferase activity in vivo and confers an agedependent neuropathy.
Submitted By: Ellen Burns, Medical Liaison

The very impressive title is the name of an article published in Human Molecular Genetics, 2005, Vol. 14, No. 22. pages 3507-3521.

The primary author of this publication is Alexander McCampbell, who is responsible for the development of the mouse model for HSN-1. Others whose expertise contributed to the report include Dr. Robert H. Brown, Junior, Director of the Day Laboratory for Neuromuscular Research, Charlestown, Massachusetts and Dr. Teresa M. Dunn, Department of Biochemistry and Molecular Biology, Uniformed Services University of the Health Sciences, Bethesda, Maryland.

Mutations in enzymes involved in sphingolipid metabolism cause a variety of neurological disorders, but how this happens, at the cellular level, is not known.

A mutated gene has been associated with HSN-1. It is identified as SPTLC1. Genes make proteins; proteins make enzymes. SPTLC1 encodes one subunit of the serine palmitoyltransferase enzyme (SPT), the rate-limiting enzyme in sphingolipid synthesis. This enzyme is known to affect the production of a fatty substance (glycosyl ceramide) in the body. HSN-1 patients have reduced SPT activity.

As we know, hereditary sensory and autonomic neuropathy type one (HSN-1) is an adult onset, autosomal dominant neuropathy (a parent must have the mutated gene for it to be transmitted to a child, but only one parent must have the gene). HSN-1 patients have sensory and motor loss and often have ulcers, weakness, and poor muscle reflexes. Both myelinated and unmyelinated nerve fibers are affected. The nerves of the dorsal root ganglia of the lumbosacral region (the lower back) are most severely affected.

Earlier experiments involving cell cultures indicated that mutant SPTLC1 inhibits SPT activity. In this study, transgenic mice (mice with a gene added) were created to over express either normal SPTLC1 or mutant SPTLC1. The mice with an added mutant gene developed age-dependent weight loss and mild sensory and motor impairments. Aged mice with the mutant genes lost myelinated nerves in the dorsal and ventral roots of the spinal cord. The mice did not develop skin ulcers on the toes and fingers, but they did develop decreased sensitivity to thermal pain (heat). The overall neurological involvement in the diseased mice appears less severe than the advance stages of the disease in patients.

The mice that have the altered genes are a new mouse model of peripheral neuropathy and confirm the link between mutant SPT and nerve dysfunction. What is still unknown is if the biochemical changes cause the pathology of the disease.

It is noted in the paper that another dominantly inherited, hereditary sensory neuropathy with ulcers, Charcot-MarieTooth is also caused by a genetic mutation that disrupts sphingolipid metabolism in another way.

More work needs to be done with the mice to further define the exact mechanism of the disease. Alex has proposed other testing that will continue at the Day Lab to answer some of the questions that have been raised.