Institute of Human Genetics Cologne, Germany

How the modified expression of a gene compensates the loss of another gene:
Plastin 3 protects against SMA

In the latest issue of Science (Oprea et al. April 25, 2008) Brunhilde Wirth and her group from the Institute of Human Genetics in Cologne, Germany reported the identification of the first modifier gene that is able to fully protect individuals from developing spinal muscular atrophy (SMA). These individuals are fully asymptomatic despite the fact that they carry homozygous SMN1 deletions, the typical mutation causing SMA.
Although patients from multiplex SMA families usually present with very similar clinical pictures, there are rare instances in which siblings with identical SMN1 and SMN2 alleles have completely different phenotypes: affected versus fully asymptomatic. This discrepancy suggests the influence of independent modifying factors capable of protecting against SMA.
By comparing the whole transcriptom (all expressed genes in a certain tissue) between unaffected and affected SMN1-deleted siblings Gabriela Oprea, PhD student in B. Wirth’s lab identified Plastin 3 to be highly expressed in all unaffected but not in the affected counterparts. Plastin 3 is normally expressed in all solid tissues including spinal cord, but not in blood. All unaffected SMN1-deleted individuals are females and interestingly also the gene Plastin 3 is localized on the sex-determining X-chromosome. The molecular cause for this gender specific protection remains, despite extensive search of the group still unknown. They found that Plastin 3 is highly expressed in spinal cord, associates with SMN, and both SMN and Plastin 3 are part of large multiprotein complex in spinal cord. The two proteins are present at similar subcellular locations in motor neurons and increase in expression during neuronal differentiation. Plastin 3 influences the dynamics of actin, which is important in axonal out growth and guidance. Knock-down of Plastin 3 severely affects axonal growth whereas over-expression induces axonal growth. Most importantly, over-expression of Plastin 3 rescues the axonal growth defects caused by reduced SMN levels in neuronal differentiated cells, in primary motor neurons of SMA mouse embryos (experiments performed together with W. Rossoll in G. Bassell’s lab, Atlanta) and in an in vivo zebrafish SMA-model (experiments performed together with M. McWorther in C. Beattie’s lab, Ohio). In summary, both the genetic and functional studies strongly support a protective role of Plastin 3 against SMA.
These results shed new light onto the debate about the most likely pathogenic defect underlying SMA. The data presented strongly support the view that the involvement of SMN in axonal outgrowth and pathfinding is the major pathogenic defect of SMA. The discovery of the Plastin 3 protein as a protector against SMA thus provides an opportunity to identify novel regulatory mechanisms that may act specifically in motoneurons, and which may be useful for the identification of the molecular pathogenesis of other motor neuron diseases as well. Eventually, the results may help to identify novel targets for SMA therapy.
This discovery signifies a major breakthrough in medical genetics in that it represents the first report ever of a strong protective modifier for a Mendelian disorder in humans.

This work was funded by the Center for Molecular Medicine Cologne and Deutsche Forschungsgemeinschaft (to BW), Families of SMA (to WR and MM) and NIH (to GB and CB).

Brunhilde Wirth
Institute of Human Genetics
University Cologne
D- 50931 Cologne
Kerpener Str. 34
Germany
e-mail:
www.uk-koeln.de/humangenetik