I didn’t expect to be doing another blog post today, but I found this story so compelling that I put off some other work to track this down. New Gene Nailed for ALS. (subscription required) My Science newsletter today had a link to a story about a new gene found that may be mutated in some cases of ALS, amyotrophic laterial sclerosis, or Lou Gehrig’s disease: This article describes the phenotype and the gene hunt a bit. It links to the research article in today’s Science as well.
From the abstract:
We identified neighbouring mutations in a highly conserved region of TARDBP in sporadic and familial ALS cases. TARDBPM337V segregated with disease within one kindred and a genome-wide scan confirmed that linkage was restricted to chromosome 1p36, which contains the TARDBP locus. Mutant forms of TDP-43 fragmented more readily than wild-type in vitro and caused neural apoptosis and developmental delay in the chick embryo in vivo. Our evidence suggests a pathophysiological link between TDP-43 and ALS.
There was a Boston Globe story about a couple of brothers in my area who were struggling with this disease. One brother had ALS and was fighting to survive, the other was fighting like crazy to find help his brother and find a cure. They did a movie that was shown on PBS, some of you may have seen it.
What would you do if you were 29 years old and found out that you only had a few years to live? The story of the remarkable events set in motion when one family confronted a disease that would transform their lives.
A subsequent story in the Globe reported that Stephen died.
These types of stories about real families remind me that this genetics stuff is not just an abstract and theoretical exercise. It is real. And another real gene may be linked to this disease, offering a new pathway to understanding.
NOTE: This is not a cure. It is a small fraction of cases. It needs more work to be confirmed. But new leads are good for this devastating illness.
Now back to this new paper:
One gene previously linked to ALS (SOD1) can explain some cases. This gene described in the current study (TDP-43 in the paper, TARDBP in the UCSC Genome browser–the link goes to my session with that gene in the browser) may explain some others. The researchers found missense mutations in exon 6 from a family affected by ALS, in a region highly conserved across several species. They looked in this region in other British ALS patients with sporadic (not familial) disease and found a different mutation 18-base pairs upstream of the first one. No mutations in this gene were found in 500 controls. Another scan from Australian sporadic cases found another nearby mutation in exon 6. One non-synonymous change was found in a control individual in this group, at another site.
The group made constructs with the mutant forms of the gene and expressed in cell culture, but this didn’t seem to increase cell death or protein aggregation. But they expressed them in chick embryos and found an impact on development. They conclude: “These results suggest a toxic gain of function or dominant negative effect of mutant TDP-43.”
I’m sure they will do experiments with mice next–I will be watching for that paper. It will be important to continue to pursue this, because this data diverges from some other work on this gene. When I was at the UCSC page I followed the links from the gene details page to the Genetic Associations Database (GAD) and the HuGE database. One of the papers at HuGE firmly states that this gene was NOT associated with either ALS or the frontotemporal dementia that GAD described.
Neuronal inclusion protein TDP-43 has no primary genetic role in FTD and ALS. But that paper is not available to me right now, so I can’t speak to it. The authors of the new Science paper refer to this earlier work, and mention that the new mutations they find are rare.
Fascinating stuff. Looking forward to more about this story.
Sreedharan, J., Blair, I.P., Tripathi, V.B., Hu, X., Vance, C., Rogelj, B., Ackerley, S., Durnall, J.C., Williams, K.L., Buratti, E., Baralle, F., de Belleroche, J., Mitchell, J.D., Leigh, P.N., Al-Chalabi, A., Miller, C.C., Nicholson, G., Shaw, C.E. (2008). TDP-43 Mutations in Familial and Sporadic Amyotrophic Lateral Sclerosis. Science DOI: 10.1126/science.1154584