UM researchers have identified a genetic variant linked to a rare form of paraplegia
Stephan Züchner, M.D., Associate Professor for Human Genetics and Neurology, and Director of Center for Human Molecular Genetics at the Hussman Institute for Human Genomics
UM researchers have identified a genetic variant linked to a rare form of paraplegia in a paper titled, “Mutations in the ER-shaping protein reticulon 2 cause the axon-degenerative disorder hereditary spastic paraplegia type 2” published online January 10, 2012 in the Journal of Clinical Investigation. The article also received recognition through a special editorial in the journal, as well as on its Facebook page. It will be published in the print edition of the journal February 1, 2012.
Stephan Züchner, M.D., Associate Professor for Human Genetics and Neurology, and Director of Center for Human Molecular Genetics at the Hussman Institute for Human Genomics, is a co senior-author for the paper. The participating collaborators include scientists from the US, Italy, UK, Germany, and Japan.
Hereditary Spastic Paraplegia (HSP) represents a group of inherited neurodegenerative disorders characterized by progressive weakness and spasticity of the legs. The disease is caused by a progressive degeneration of long nerve fibers (axons) in the spinal cord. No therapy is available for this disorder.
Mutations in more than 30 genes have been linked to HSPs. In patients with HSP from Northern Europe and America, the most commonly affected genes are spastin (SPG4), atlastin-1 (ATL1), and receptor expression-enhancing protein 1 (REEP1). The latter one was identified by Drs. Züchner and Margaret A. Pericak-Vance, Ph.D. in 2006. As these genes encode proteins that cooperate to shape a cellular structure called endoplasmic reticulum (ER) into sheets and tubules, it has been suggested that abnormal ER morphogenesis can cause HSP.
Züchner and colleagues have now provided further support for this hypothesis as they have identified mutations in the gene reticulon 2 (RTN2), part of a family of prototypic ER-shaping proteins, in individuals with HSP type 12. This was achieved by a combination of linkage analysis and exome sequencing. Analysis of the function of wild-type reticulon 2 and a truncated form of the protein that was identified in patients with spastic paraplegia type 12, indicated that only the wild-type protein localized to the ER and interacted properly with the protein spastin. These data directly link a new gene to HSPs and further support a likely underlying disease mechanism.
Züchner is hopeful this research will have implications beyond HSP as well. Even the identification of a rare gene, like in this case with HSP, can have larger implications, he explained.
“We hope this paper shows how human genetics can help in understanding spinal cord biology, degeneration, and injury,” Züchner said. For instance, another reticulon protein, RTN4 (better known as ‘NoGo’), has long been a candidate for treatment of spinal cord injury and the current study might provide new clues for this line of research.
Dr. Züchner is currently researching HSP through a $3.12M NIH grant titled “Genome Studies in Hereditary Spastic Paraplegia”. Züchner and his team will use the funding to study relatively small families and individual cases with HSP in order to identify additional missing genes in HSP. Other significant investigators on the paper include Gladys Montenegro, M.S., and Adriana Rebelo, Ph.D., from the University of Miami, Antonio Orlacchio, Ph.D., University of Rome, Italy, and Evan Reid, Ph.D., University of Cambridge, UK.