Miller School Researchers Identify a Genetic Variant Linked to Rare Form of Paraplegia

The article, titled “Mutations in the ER-shaping protein reticulon 2 cause the axon-degenerative disorder hereditary spastic paraplegia type 2,” also received recognition through a special editorial in the journal. It will be published in the print edition of the journal February 1.

Stephan Züchner, M.D., associate professor of human genetics and neurology and director of the Center for Human Molecular Genetics at the John P. Hussman Institute for Human Genomics, is a co-senior author on the paper. Participating collaborators include scientists from the U.S., Italy, the United Kingdom, 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 was identified by Züchner and Margaret A. Pericak-Vance, Ph.D., director of the John P. Hussman Institute and the Dr. John T. Macdonald Foundation Professor of Human Genomics, 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, as in this case with HSP, can have broader 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 $3.12 million 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, research associate, Adriana Rebelo, Ph.D., post-doctoral associate, Antonio Orlacchio, Ph.D., University of Rome, Italy, and Evan Reid, Ph.D., University of Cambridge, U.K.