Scripps research scientists find new genetic mutation that halts the developmen...(ole in lupus susceptibility. The stu...),Health

The study suggests genetic-mapping studies need to adequately distinguish between predisposing or suppressive alleles or alternate gene forms, and that other lupus-related loci might also be associated with suppressive alleles. In addition to traditional predisposing genes, disease-suppressing genes and spontaneous mutations, as in the case for CoroLmb3, are likely to be important contributors to an entire repertoire of genetic variations that could help alter the onset and severity of the disease in lupus patients.

Obviously, these types of variations will further complicate the identification of susceptibility genes, Kono added. However, as in the case of disease-suppressing genes such as we found in our study, their identification can provide important clues to pathogenesis and possibly therapy.

The Scripps Research scientists found the mutation on a single genetic locus-the position of a gene on a chromosome-called Lmb3 that plays a major role in modulating autoimmunity in transgenic mice. The cloned version of the Lmb3 mutation resulted in developmental and functional alterations in T cells, including reduced migration, survival, and activation. The study also showed that the Lmb3 autoimmune-suppressing phenotype could be transmitted only through Coro1aLmb3 T cells.

The fact that its action appears to be somewhat specific for T cells is unusual, Kono said. Because we were able to show that blocking CoroLmb3 has specific effects, this work suggests other cytoskeleton proteins might prove to be good targets. This opens up an area that hasnt really been considered, and gives more impetus to study these genes for autoimmunity.

Because the actin cytoskeleton is essential for many crucial cellular functions and involves complex regulatory mechanisms in specific cell types, these new findings highlight the importance of actin regulation in lupus pa
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