Jonathan Haines, Ph.D.
Study identifies gene linked to inherited ALS
A multi-center team, including Vanderbilt's Center for Human Genetics Research, has identified a new genetic culprit for some inherited forms of amyotrophic lateral sclerosis (ALS).
The findings, reported in the Feb. 27 issue of Science, suggest new avenues for exploring the biological mechanisms underlying the disease, which could lead to novel therapeutic targets, said study contributor Jonathan Haines, Ph.D., director of the Vanderbilt center.
ALS, sometimes called “Lou Gehrig's disease,” is a progressive disorder marked by the degeneration and death of motor neurons. As the motor neurons die, the brain's ability to initiate and control muscle movement is lost, eventually leaving patients totally paralyzed.
About 20,000 Americans have ALS, with 5,000 new cases occurring in the United States each year, according to the National Institute of Neurological Disorders and Stroke. In about 10 percent of ALS cases, the disease is inherited — so-called familial ALS (FALS) — but only a few genes have been identified as causing FALS.
“ALS is a terrible disease, and the genetics has been surprisingly hard to dissect,” Haines said. “Even with this exciting finding, the majority of genes underlying FALS remain to be identified.”
The current studies began with a family with four ALS-affected members. The researchers were able to pinpoint a suspicious region on chromosome 16 that contained 56 candidate ALS genes.
They sequenced each of these genes and found a variant (mutation) in a gene called FUS/TLS (fused in sarcoma/translated in liposarcoma). The variant was present in both gene copies (homozygous) in the four family members with ALS. It was present in one gene copy (heterozygous) in asymptomatic family members, suggesting recessive inheritance of the disease. The mutation was not present in 1,446 control DNA samples.
Next, the investigators sequenced the FUS/TLS gene in two other ALS families whose disease had previously been genetically linked to chromosome 16. They found additional, different genetic variations in FUS/TLS in these families. They then continued their exploration of the FUS/TLS gene in another 209 ALS families and in 293 sporadic (non-inherited) ALS cases.
Overall, the researchers detected 13 different FUS/TLS mutations in 17 families with FALS. No mutations were found in samples from patients with sporadic ALS, nor in samples from control individuals.
The FUS/TLS protein functions in diverse cellular processes, including RNA metabolism, and it has been implicated in tumor development. It is normally located predominantly in the cell nucleus.
In studies of autopsy tissue from one FALS patient with a mutation in the FUS/TLS gene, the researchers found that the protein was present at high levels in the cell cytoplasm (in the cell, but outside the nucleus). Using cultured cells, the team observed that the mutant FUS/TLS protein was not correctly routed to the nucleus and accumulated inside cells.
The cytoplasmic retention and apparent aggregation of FUS/TLS is reminiscent of models for FALS pathogenesis involving mutations in the superoxide dismutase gene (SOD1).
The findings suggest that cytoplasmic protein aggregation and defective RNA metabolism may be common pathogenic mechanisms for ALS and possibly other neurodegenerative disorders, Haines said.
“The current report represents the culmination of many years worth of work by many investigators to finally identify another gene for ALS.”
The investigators estimate that mutations in FUS/TLS will account for about 5 percent of FALS cases, comparable to the frequency of mutations in another FALS gene (TDP43).
Mutations in SOD1 cause about 20 percent of FALS cases.
The National Institutes of Health and multiple foundations supported the research.
Haines is the T. H. Morgan Professor in Human Genetics and professor of Molecular Physiology & Biophysics.