A multinational study group, using cutting-edge "exome sequencing" technology, has uncovered five mutations in the valosin-containing protein (VCP) gene and implicated them as molecular causes of some familial forms of ALS (amyotrophic lateral sclerosis, or Lou Gehrig's disease).
Mutations in the VCP gene previously have been shown to cause inclusion-body myopathy associated with Paget's disease of bone and/or frontotemporal dementia (IBMPFD). (MDA classifies this disease as a form of inclusion-body myositis.)
The addition of the VCP gene to the growing list of genes associated with ALS provides additional evidence and another angle through which scientists can probe the underpinnings of this disease.
About the new findings
In study results published Dec. 9, 2010, in the journal Neuron, a research team funded in part by MDA identified five mutations in the VCP gene as the molecular cause in some forms of familial (inherited) ALS.
MDA supported Michael Benatar, associate professor of neurology and epidemiology at the University of Miami, for this work.
The group studied four individuals representing four generations of an Italian family, each of whom had a confirmed diagnosis of ALS and in whom the genes commonly associated with ALS (SOD1, TDP43 and FUS) were ruled out as the cause of disease.
Using a new technique called exome sequencing, the investigators identified and implicated a VCP gene mutation as the underlying cause of the family's ALS.
They subsequently examined 210 ALS-affected individuals from unrelated families, as well as samples from 1,205 unaffected individuals who made up the "control" group, and found four additional VCP mutations present in approximately 1 percent to 2 percent of familial ALS cases – a frequency, the researchers wrote, comparable to that of cases caused by TDP43 and FUS.
About VCP and TDP43
VCP performs a variety of vital functions within the cell, one of which is helping support the ubiquitination/protein degradation pathway responsible for the breakdown and disposal of malformed, non-functional or otherwise unwanted proteins.
This natural cellular waste disposal system, called autophagy ("self-eating"), is a necessary function in maintaining the health of the cell.
Results from previous studies in IBMPFD have suggested that disease-causing mutations in VCP may impair the protein's crucial role in the cell's natural cleanup and garbage disposal system, leading to the accumulation in neurons of protein clumps called inclusions.
Previous studies have shown that TDP43-containing inclusions are present in motor neurons in both IBMPFD and a number of forms of ALS.
It's also been demonstrated in mouse models and in cell culture studies in the laboratory that VCP mutations affect TDP43 protein function, in part by causing the protein to move from where it normally resides in the cell's nucleus out to the surrounding cytoplasm. TDP43 structural and functional changes also have been observed in the spinal cord motor neurons (nerve cells) of mice with VCP mutations.
However, the molecular mechanisms by which mutations in the VCP gene cause motor neuron degeneration and the various features of IBMPFD, and VCP-mediated ALS are not yet clear.
"I don't think we can really draw any mechanistic conclusions from the data we've published, although tantalizing hypotheses and possibilities have emerged," Benatar said, noting that the findings show that VCP mutations may underlie a motor neuron disease that produces physical and biochemical characteristics shared by individuals with IBMPFD and in those with "more classical familial ALS."
"Given the connection between VCP and TDP43, it is tempting to speculate that mutations in VCP are responsible for TDP43 mislocalization and that this in turn leads to neurodegeneration, but we have not yet shown this to be the case."
About exome sequencing
Exome sequencing is faster and less expensive than previous generations of technology aimed at revealing the chemical "letters" that make up the human genome, and searching for genes associated with human diseases.
As opposed to whole genome sequencing, in which a readout of an individual's entire genome is produced, the new strategy decodes only the stretches of DNA called "exons," which contain instructions used in protein synthesis. ("Introns," DNA regions that do not contain information used to make proteins, are ignored.)
Although exons make up only about 1.5 percent of the genome, the vast majority of disease-causing mutations occur in these sections.
"Our data demonstrate the utility of exome sequencing in determining the genetic causes of familial neurodegeneration," the researchers wrote, noting that the technique is a "realistic strategy" for uncovering the genetic variants responsible for disease in small groups of individuals.
Meaning for people with ALS
The recognition that mutations in VCP can cause ALS provides "a unique opportunity to gain insight" into the ALS disease process, Benatar said.
Also valuable is the team's initial evidence that impairment of the cell's protein degradation pathway is a causative factor for the disease.
Although the frequency of VCP mutations in familial ALS must be confirmed in independent testing, the study authors wrote, it appears "comparable to that reported for TDP43 and FUS mutations, highlighting the relative significance of this gene as a cause of familial ALS."
Overall, the findings provide key information and boost scientists' understanding of the ALS disease process. Such foundational knowledge is vital to determining the disease's molecular underpinnings and designing effective therapies to slow, and ultimately cure, ALS.