Gene Identified

The Gene Causing the Deater Disease Is Identified!
Important Research Results Published
Ellen Burns, Vice President and Medical Liaison

In the March 2001 edition, Volume 27, of the prestigious scientific journal Nature Genetics, two articles were published that were the culmination of years of research involving the Deater family and other families with a degenerative neurologic disease.

One article, Mutations in SPLTC1, encoding serine palmitoyltransferase, long chain base subunit-1, cause hereditary sensory neuropathy type I, was submitted by Jennifer Dawkins and her team at the Neurobiology Laboratory of University of Sydney, New South Wales, Australia, under the leadership of Garth Nicholson. For some years, now, this Australian group has been collaborating with the research group from the Day Neuromuscular Laboratory in Charlestown, Massachusetts to find the exact gene that causes the disease that affects the Deater family. This disease is known in medical circles as HSN I (Hereditary Sensory Neuropathy type I). In fact, some medical textbooks and research articles specifically refer to earlier published research on our family.

In the Nature Genetics article, the Australian researchers identify the specific gene, SPTLC1, on chromosome 9 (more specifically: 9q22.3), that is mutated, or different, in people who have HSN1. These researchers studied 11 families and found three different mutations in the gene, among all the affected family members. Everyone who had the disease had a gene mutation in this gene. Because of the collaboration with the Day Lab research team, these researchers had access to the DNA samples from members of the Deater family, and to previous research done by Khemissa Bejaoui and others in the Day Lab.

The gene with the mutations associated with HSN1, identified as SPTLC1, is a gene that had been previously studied, and therefore the researchers know what the gene does. Genes make proteins; proteins make enzymes. SPTLC1 encodes subunit 1 of the serine palmitoyltransferase enzyme. This enzyme is known to affect the production of a fatty substance (glycosylceramide) in the body. In the article, the researchers speculate that the increased production of this fatty substance causes the death of certain cells and so may destroy nerve cells and cause degeneration of the nerves resulting in the disease HSN1.

The other article in the March 2001 Nature Genetics that is of particular interest to the family is SPTLC1 is mutated in hereditary sensory neuropathy, type 1. This article was written by Khemissa Bejaoui as a result of the research done at the Day Neuromuscular Laboratory at Massachusetts General Hospital, Charlestown, Massachusetts. Dr. Bob Brown is the Director of the Lab. In this article, Khemissa reports on research done on the DNA provided by members of the Deater family, and other families also affected with HSN1. The Day Lab, through Khemissa’s research, reports co-discovery with the Australian group that the gene SPTLC1, which encodes a subunit of serine palmitovltransferase is mutated in HSN1.

The Day Lab research found mutations in two different areas of the gene, and demonstrated complete linkage with the disease in our family; that is, everyone who had the mutation of the gene had the disease, and everyone who has the disease has the mutation. There were no mutations in people who did not have the disease.

Khemissa also explains that the gene produces a protein product (LCB1) which forms a complex with at least one other protein (LCB2). It is known that the enzyme made by these protens is made active primarily by LCB2. Khemissa surmises that the mutant LCB1 protein has either (1) acquired a new action, or that it (2) somehow changes the levels of SPT activity. Since SPT affects the production of a fatty substance (glycosyl ceramide) in the body, it is possible that LCB1 may either promote, or fail to inhibit, the action of LCB2. The result may be an increase in the production of the fatty substance that then causes nerve cell death, resulting in the disease HSN1. Not all the families studied by the Day Lab researchers demonstrated linkage to this gene. The Deater family did show a mutation in this gene. Another family also showed a mutation in this gene, but at a different location (base) on the same gene. Khemissa indicates that more work needs to be done to examine the gene (on chromosome 14) that is responsible for LCB2. The research is continuing.