Mutations in valosin-containing protein (VCP) come in many guises. VCP deficiency can manifest as symptoms in the muscles, bones, or brain, and in the November 9 Neuron, a multinational team of researchers added motor neurons to that list. In hunting for mutations that cause amyotrophic lateral sclerosis (ALS), they discovered that VCP mutations, long thought to spare the spine, are instead a cause of inherited ALS. The researchers estimate that VCP mutations are responsible for 1 to 2 percent of familial ALS cases, in addition to causing the awkwardly named complex IBMPFD—inclusion body myopathy, Paget’s disease, and frontotemporal dementia (Watts et al., 2004). The work gives ALS researchers a new gene to play with and suggests that doctors should consider ALS symptoms in cases of IBMPFD, and vice versa.

In broadening the IBMPFD phenotype, this discovery continues a trend of neurodegenerative categories bleeding into one another. Scientists have already accepted that ALS, which affects motor neurons, and frontotemporal dementia (FTD), which affects cortical neurons, sit at opposite ends of a disease spectrum across the TDP-43 proteinopathies (see ARF related news story on Neumann et al., 2006). “Hang on to your hat,” said J. Paul Taylor of St. Jude Children’s Research Hospital in Memphis, Tennessee. “The spectrum that exists between ALS and FTD is just the beginning of the types of connectedness in age-related diseases.” Taylor collaborated on the ALS VCP study. In fact, the connections extend into a juvenile condition, spinal muscular atrophy (SMA), as well. Through its effects on the location of SMN1, TDP-43 is also linked to SMA (see ARF related news story on Shan et al., 2010), and SMA and ALS can both result from ataxin-2 polymorphisms (see ARF related news story on Elden et al., 2010).

Leading the investigation were joint senior authors Gabriella Restagno of the Ospedale Infantile Regina Margherita Sant Anna in Turin, Italy; Adriano Chiò of the University of Turin; and Bryan Traynor of the National Institute on Aging. The researchers used a new form of genetic analysis, exome sequencing, to find the VCP mutations without the need to study a large, extended pedigree. Starting with an Italian family, they eventually expanded their analysis to other families and discovered four different VCP mutations in people who had classical ALS symptoms and pathology. Afflicted relatives had a mix of ALS, parkinsonism, dementia, Paget’s disease, and muscle weakness. The geneticists found no VCP mutations in healthy control DNA samples. Joint first authors Janel Johnson and Yevgeniya Abramzon of the National Institute on Aging in Bethesda, Maryland; Jessica Mandrioli of the University of Modena in Italy; and Michael Benatar of Emory University School of Medicine in Atlanta, Georgia, performed much of the work.

The Gene Wears Many Hats
VCP not only causes many kinds of disease, it performs many cellular tasks. “It has probably close to a dozen defined cellular activities, and that likely is just the tip of the iceberg,” Taylor said. The protein participates in transcription, cell division, Golgi assembly, and autophagy, to name a few, but even so, “it is basically a one-trick pony,” Taylor said. Wherever it is, VCP’s job is to untangle ubiquitinated proteins from multi-component complexes so the tagged protein can be destroyed by the proteasome. For example, in the endoplasmic reticulum, if one protein in a complex is misfolded, VCP helps to retrieve and degrade it.

VCP mutations cause a “completely penetrant disorder of variably penetrant phenotypes,” said Chris Weihl of Washington University in St. Louis, Missouri, who was not involved in the Neuron study. Inclusion body myopathy causes muscle weakness, Paget’s disease breaks down bone, and frontotemporal dementia degrades the frontal cortex, interfering with cognition. Other features, such as cataracts, cardiomyopathy, and liver degeneration, occasionally join the mix. The same exact mutation can cause wildly varying presentations. “Within the same family, grandma could have dementia, mom could have pure muscle weakness, and the affected siblings could have Paget’s disease,” Weihl said. However, the pathology is similar: All share inclusions of ubiquitinated proteins, and TDP-43 aggregates are common as well (reviewed in Weihl et al., 2009).

This linking of VCP to ALS completes a picture of VCP disease running throughout the body’s movement machinery. VCP disease “is a true disorder of the motor system, branching all the way from the initiation of movement in the frontal cortex, through the spinal cord to the muscle, and even to the skeletal system itself,” Weihl said.

The publication bucks a common belief among neurologists. It is that VCP mutations and motor neuron disease do not coincide. Indeed, the authors write, a diagnosis of ALS with VCP mutation was often considered to be erroneous (Kimonis et al., 2008). Denervation in IBMPFD patients is quite rare, Weihl said.

Could the study authors have mistaken their ALS diagnoses? Christopher Shaw of King’s College London, United Kingdom, who was not involved in the study, analyzes the question in a Neuron Preview. He concluded, the people in the study truly had classical ALS. “Several of the authors are highly experienced neurologists who elicited signs of upper and lower motor neuron degeneration,” confirming the diagnosis, Shaw wrote. He added that the people with ALS in the study died or required ventilation within a few years of diagnosis, as is normal for ALS, whereas IBM does not normally cut short a person’s life. The researchers clinched their case with autopsy tissue from a patient, which clearly showed that ALS pathology carried a VCP-R155H mutation. “There was no doubt, whatsoever, that this was ALS,” Traynor said.

Closing in on VCP
The researchers started their search for ALS mutations with an Italian family in which three members had the disease, but they never would have found the VCP gene if not for modern, fast sequencing technology. Normally, geneticists look for genetic associations by linkage analysis, which requires large family trees. ALS fells its victims so quickly that researchers rarely find a large enough family with affected individuals.

Instead of linkage analysis, the researchers used exome sequencing. This is a fairly new approach that focuses on the 1 percent of the genome that actually encodes proteins (Ng et al., 2009). They collected DNA from two afflicted family members and sheared it. Then, using a kit of exome oligonucleotides as bait, they isolated only the protein-coding fragments for sequencing and reassembled the exomes.

Each person has some 100,000 variants that would show up in this kind of analysis, Traynor said. “You have to whittle that down to a much more manageable number.” The geneticists eliminated single nucleotide polymorphisms already present in the dbSNP and 1000 Genomes databases. They also assumed that the disease-linked variant would be common among the three family members with ALS, narrowing the field to 33 variants. Via further analysis based on linkage groups, variants in control subjects, and mutations predicted to alter protein structure, the researchers got the number of possible ALS mutations down to four.

And that is where they lucked out, because one of the four—a VCP-R191Q mutation—was already known to cause the TDP-43 proteinopathy IBMPFD (Ju and Weihl, 2010; Watts et al., 2004). The scientists have not analyzed the other three possibilities.

To prove VCP mutations cause ALS, the scientists sequenced the VCP gene in 210 familial ALS cases and 78 other ALS cases that were confirmed by autopsy. They discovered four other instances of VCP mutations—another R191Q, R159G, D592N, and the R155H mutations. None of 1,544 control sequences included a VCP mutation.

Answers and Questions
VCP joins a handful of genes that together explain perhaps one-third of inherited ALS cases. SOD1 (Rosen et al., 1993) has the lion’s share at 15 to 20 percent, while TDP-43, FUS, and VCP each account for 1 to 4 percent of familial cases. It is believed that the ninth chromosome harbors yet another ALS gene, and several other mutations coincide with non-classical forms of motor neuron disease.

“In retrospect, VCP was a very good candidate gene for screening in ALS,” Shaw wrote. For example, a mutation in VPS54, which performs similar functions to VCP, causes ALS-like symptoms in the wobbler mouse (Schmitt-John et al., 2005). TDP-43 also appears to interact with VCP (see ARF related news story; ARF related news story on Ritson et al., 2010; Custer et al., 2010; Ju and Weihl, 2010).

How might VCP mutations cause disease? Because knocking out VCP is lethal, and people with the mutations live healthy lives for many decades, Taylor said, “these missense mutations must not alter VCP function tremendously.” The protein functions as a hexamer, and the mutations sit at junctions where monomers would meet. Therefore, Traynor suggested, the disease-linked mutations might alter the hexamer’s structure. As far as the TDP-43 connection, Taylor suspects VCP normally pulls apart TDP-43-containin ribonucleoprotein complexes, which accumulate if the disassembly goes awry.

The big question, though, is how the same mutations express themselves clinically in so many ways. It’s as if 10 chefs started with the same recipe and ingredients, but produced startlingly different dishes. And the rumor at conferences, sources told ARF, is that parkinsonism will soon join the IBMPFD-ALS roster. No one knows why VCP mutations can lead to such different outcomes. Perhaps, Weihl speculated, other genetic, epigenetic, or environmental factors add the seasoning that alters the dish.

Taylor suggested that examining the different systems where VCP works could help scientists determine which go wrong in different manifestations. The authors also recommend that doctors monitor people with ALS for other signs of IBMPFD. On a broader note, doctors and scientists often feel compelled to classify diseases into neat bins; one for motor neuron disease, one for myopathy, one for dementia, and so on. But Traynor predicted that future exome sequencing would not only find new genes but, like this one, find new roles for old ones. “In the next year to 18 months, we are going to see an avalanche of exome sequencing projects that show the merging,” he said. “Those dividers between the bins are going to start going away.”—Amber Dance


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News Citations

  1. New Ubiquitinated Inclusion Body Protein Identified
  2. Latest TDP-43 Mouse Unites ALS and SMA Pathways
  3. ALS—A Polyglutamine Disease? Mid-length Repeats Boost Risk
  4. Honolulu: TDP-43 Gets a Place in the Sun
  5. Paper Alert: Malformed Mitochondria in the Latest TDP-43 Mouse

Paper Citations

  1. . Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein. Nat Genet. 2004 Apr;36(4):377-81. Epub 2004 Mar 21 PubMed.
  2. . Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science. 2006 Oct 6;314(5796):130-3. PubMed.
  3. . Altered distributions of Gemini of coiled bodies and mitochondria in motor neurons of TDP-43 transgenic mice. Proc Natl Acad Sci U S A. 2010 Sep 14;107(37):16325-30. Epub 2010 Aug 24 PubMed.
  4. . Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature. 2010 Aug 26;466(7310):1069-75. PubMed.
  5. . Valosin-containing protein disease: inclusion body myopathy with Paget's disease of the bone and fronto-temporal dementia. Neuromuscul Disord. 2009 May;19(5):308-15. PubMed.
  6. . VCP disease associated with myopathy, Paget disease of bone and frontotemporal dementia: review of a unique disorder. Biochim Biophys Acta. 2008 Dec;1782(12):744-8. Epub 2008 Sep 18 PubMed.
  7. . Targeted capture and massively parallel sequencing of 12 human exomes. Nature. 2009 Sep 10;461(7261):272-6. PubMed.
  8. . Inclusion body myopathy, Paget's disease of the bone and fronto-temporal dementia: a disorder of autophagy. Hum Mol Genet. 2010 Apr 15;19(R1):R38-45. PubMed.
  9. . Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature. 1993 Mar 4;362(6415):59-62. PubMed.
  10. . TDP-43 mediates degeneration in a novel Drosophila model of disease caused by mutations in VCP/p97. J Neurosci. 2010 Jun 2;30(22):7729-39. PubMed.
  11. . Transgenic mice expressing mutant forms VCP/p97 recapitulate the full spectrum of IBMPFD including degeneration in muscle, brain and bone. Hum Mol Genet. 2010 May 1;19(9):1741-55. Epub 2010 Feb 10 PubMed.

External Citations

  1. dbSNP
  2. 1000 Genomes

Further Reading


  1. . Clinical heterogeneity in 3 unrelated families linked to VCP p.Arg159His. Neurology. 2009 Aug 25;73(8):626-32. PubMed.
  2. . ALS and FTLD: two faces of TDP-43 proteinopathy. Eur J Neurol. 2008 Aug;15(8):772-80. PubMed.
  3. . Clinical studies in familial VCP myopathy associated with Paget disease of bone and frontotemporal dementia. Am J Med Genet A. 2008 Mar 15;146A(6):745-57. PubMed.
  4. . Two Australian families with inclusion-body myopathy, Paget's disease of bone and frontotemporal dementia: novel clinical and genetic findings. Neuromuscul Disord. 2010 May;20(5):330-4. Epub 2010 Mar 23 PubMed.
  5. . VCP mutations causing frontotemporal lobar degeneration disrupt localization of TDP-43 and induce cell death. J Biol Chem. 2009 May 1;284(18):12384-98. PubMed.

Primary Papers

  1. . Exome sequencing reveals VCP mutations as a cause of familial ALS. Neuron. 2010 Dec 9;68(5):857-64. PubMed.
  2. . Capturing VCP: another molecular piece in the ALS jigsaw puzzle. Neuron. 2010 Dec 9;68(5):812-4. PubMed.