If there is one thing motor neurons cannot handle, it seems to be perturbations to their RNA machinery. Adding to genes with RNA-related functions in amyotrophic lateral sclerosis and spinocerebellar ataxia, the April 29 Nature Genetics online carries word of another motor neuron disorder, pontocerebellar hypoplasia, in which mutations in an RNA exosome component are to blame. Researchers at the University of California, Los Angeles, report their discovery of mutations in EXOSC3 (exosome component 3) in several people with the rare disorder. “It further emphasizes the importance of RNA metabolism [in motor neurons],” said senior author Joanna Jen.

Pontocerebellar hypoplasia (PCH) is a heterogeneous disorder that can cause degeneration of motor and cerebellar neurons in the brain and spinal cord, as well as the pons connecting the cerebellum to the cerebral cortex (Namavar et al., 2011). The prevalence of this rare autosomal recessive condition is unknown. The disease strikes infants, and many people with PCH do not survive past early childhood. Jen was approached by a family in which four children had an unusual syndrome she eventually diagnosed as PCH. “They basically had no muscle; it was like skin on bone as far as I could tell,” Jen said. The children also possessed smaller-than-average brains, with a particularly tiny cerebellum, she said.

Jijun Wan in Jen’s lab and Michael Yourshaw in the lab of collaborator Stanley Nelson were co-first authors of the study. They used linkage analysis to identify four potential locations for the faulty gene, and then applied exome sequencing to discover a missense mutation that would lead to an aspartic acid-132-alanine substitution in EXOSC3. Jen then reached out to other doctors with PCH patients for DNA samples. In a dozen other families, the team found more instances of the Asp132Ala mutation, as well as glycine-31-alanine, tryptophan-238-arginine, alanine-139-proline, a frameshift mutation, and a splice site mutation, all in the EXOSC3 gene.

Exosome component 3, also known as ribosomal RNA-processing 40 (RRP40), participates in the exosome complex that trims or degrades a variety of RNA species (reviewed in Decker, 1998). Little is known about the enzyme’s activity or substrates, Jen said, and there is only one standard assay for its function. The test relies on the fact that the exosome makes the 5.8S rRNA out of a 7S-sized precursor, so an accumulation of 7S rRNA would indicate poor exosome function. However, Wan and colleagues were unable to observe excess unprocessed rRNA in fibroblasts from one of the people with PCH. Jen suspects, therefore, that the missense mutations retain some activity. She thinks the splicing and frameshift mutations, which each occurred in parallel with missense alleles in one case, are likely to be null. Although the team was unable to obtain direct evidence for the deleterious effect of the mutation in people, they did find that knocking down the gene in zebrafish embryos resulted in small, nearly motionless fish with small brains. Providing mRNA for wild-type EXOSC3 rescued the phenotype.

“RNA keeps cropping up in motor neuron diseases,” said Daryl Bosco of the University of Massachusetts Medical School in Worcester, who was not involved in the paper. In addition to EXOSC3, genes for the tRNA splicing endonucleases TSEN2, TSEN34, and TSEN54 cause PCH (Budde et al., 2008), as do mutations in the mitochondrial arginyl-transfer RNA synthetase RARS2 (Edvardson et al., 2007). Amyotrophic lateral sclerosis genes include TAR DNA binding protein 43 (TDP-43) and fused in sarcoma (FUS), both involved in RNA regulation (see ARF related news story on Kwiatkowski et al., 2009 and Vance et al., 2009). And researchers have suggested that the RNA of hexanucleotide-expanded C9ORF72, which also causes ALS, may aggregate other RNAs and RNA binding proteins (see ARF related news story on Renton et al., 2011 and Dejesus-Hernandez et al., 2011).

Interestingly, the new paper suggests that cerebellar and motor neurons are susceptible to similar processes, commented Robert Brown, also at the University of Massachusetts Medical School. Corroborating that idea, large expansions in ataxin 2 cause spinocerebellar ataxia (SCA), but mid-length repeats increase risk for ALS (see ARF related news story on Elden et al., 2010). In addition, a hexanucleotide expansion in the nucleolar protein NOP56, which helps assemble the ribosome, causes a form of SCA that includes motor neuron pathology (Kobayashi et al., 2011).

The new work emphasizes how vulnerable motor and cerebellar neurons are to RNA defects, Jen said. As to why, researchers can only speculate. It could be because they are very active neurons, Jen suggested. In addition, both types have large cell bodies with long axons, Brown noted. It is also possible, Bosco speculated, that other types of neurodegenerative diseases are due to RNA defects, but the relevant examples have not yet been found.

“Our understanding of the population of RNAs is just in its infancy, and is expanding mightily,” Brown said. In his words, it is a “brave new world.”—Amber Dance


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News Citations

  1. New Gene for ALS: RNA Regulation May Be Common Culprit
  2. Corrupt Code: DNA Repeats Are Common Cause for ALS and FTD
  3. ALS—A Polyglutamine Disease? Mid-length Repeats Boost Risk

Paper Citations

  1. . Clinical, neuroradiological and genetic findings in pontocerebellar hypoplasia. Brain. 2011 Jan;134(Pt 1):143-56. PubMed.
  2. . The exosome: a versatile RNA processing machine. Curr Biol. 1998 Mar 26;8(7):R238-40. PubMed.
  3. . tRNA splicing endonuclease mutations cause pontocerebellar hypoplasia. Nat Genet. 2008 Sep;40(9):1113-8. PubMed.
  4. . Deleterious mutation in the mitochondrial arginyl-transfer RNA synthetase gene is associated with pontocerebellar hypoplasia. Am J Hum Genet. 2007 Oct;81(4):857-62. PubMed.
  5. . Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science. 2009 Feb 27;323(5918):1205-8. PubMed.
  6. . Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science. 2009 Feb 27;323(5918):1208-11. PubMed.
  7. . A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron. 2011 Oct 20;72(2):257-68. Epub 2011 Sep 21 PubMed.
  8. . Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron. 2011 Oct 20;72(2):245-56. Epub 2011 Sep 21 PubMed.
  9. . Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature. 2010 Aug 26;466(7310):1069-75. PubMed.

Further Reading


  1. . Molecular pathways of motor neuron injury in amyotrophic lateral sclerosis. Nat Rev Neurol. 2011 Nov;7(11):616-30. PubMed.
  2. . Amyotrophic lateral sclerosis and spinocerebellar ataxia 2. Neurology. 2011 Jun 14;76(24):2050-1. PubMed.
  3. . Expanded ATXN2 CAG repeat size in ALS identifies genetic overlap between ALS and SCA2. Neurology. 2011 Jun 14;76(24):2066-72. PubMed.
  4. . Molecular basis of amyotrophic lateral sclerosis. Prog Neuropsychopharmacol Biol Psychiatry. 2011 Mar 30;35(2):370-2. PubMed.
  5. . TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat Genet. 2008 May;40(5):572-4. Epub 2008 Mar 30 PubMed.
  6. . TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science. 2008 Mar 21;319(5870):1668-72. Epub 2008 Feb 28 PubMed.

Primary Papers

  1. . Mutations in the RNA exosome component gene EXOSC3 cause pontocerebellar hypoplasia and spinal motor neuron degeneration. Nat Genet. 2012 Apr 29; PubMed.