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. 2012 Apr 29;44(6):704-8.
doi: 10.1038/ng.2254.

Mutations in the RNA exosome component gene EXOSC3 cause pontocerebellar hypoplasia and spinal motor neuron degeneration

Jijun Wan  1 , Michael Yourshaw, Hafsa Mamsa, Sabine Rudnik-Schöneborn, Manoj P Menezes, Ji Eun Hong, Derek W Leong, Jan Senderek, Michael S Salman, David Chitayat, Pavel Seeman, Arpad von Moers, Luitgard Graul-Neumann, Andrew J Kornberg, Manuel Castro-Gago, María-Jesús Sobrido, Masafumi Sanefuji, Perry B Shieh, Noriko Salamon, Ronald C Kim, Harry V Vinters, Zugen Chen, Klaus Zerres, Monique M Ryan, Stanley F Nelson, Joanna C Jen
Affiliations

Mutations in the RNA exosome component gene EXOSC3 cause pontocerebellar hypoplasia and spinal motor neuron degeneration

Jijun Wan et al. Nat Genet. .

Abstract

RNA exosomes are multi-subunit complexes conserved throughout evolution and are emerging as the major cellular machinery for processing, surveillance and turnover of a diverse spectrum of coding and noncoding RNA substrates essential for viability. By exome sequencing, we discovered recessive mutations in EXOSC3 (encoding exosome component 3) in four siblings with infantile spinal motor neuron disease, cerebellar atrophy, progressive microcephaly and profound global developmental delay, consistent with pontocerebellar hypoplasia type 1 (PCH1; MIM 607596). We identified mutations in EXOSC3 in an additional 8 of 12 families with PCH1. Morpholino knockdown of exosc3 in zebrafish embryos caused embryonic maldevelopment, resulting in small brain size and poor motility, reminiscent of human clinical features, and these defects were largely rescued by co-injection with wild-type but not mutant exosc3 mRNA. These findings represent the first example of an RNA exosome core component gene that is responsible for a human disease and further implicate dysregulation of RNA processing in cerebellar and spinal motor neuron maldevelopment and degeneration.

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Conflict of interest statement

Competing financial interests

The authors declare no competing financial interests.

Figures

Figure 1
Figure 1
Neuroimaging, neuromuscular, and pathological features in Family 1. a. Sagittal T2- and b. coronal T1-weighted images from the oldest surviving sibling who is now 18 years old demonstrate the presence of all cerebellar lobules yet with marked atrophy compared to T1-weighted e. sagittal and f. coronal images from an age-matched normal male. c. Sagittal and d. coronal T1-weighted images from the youngest surviving sibling who is now 9 years old demonstrate cerebellar volume loss comparable to a.-b. in contrast to g. sagittal and h. coronal T1-weighted images from an age-matched normal male. Needle EMG tracings in the i. left triceps muscle of the 18-year-old sibling and j. right vastus lateralis muscle of the 9-year-old sibling showed neurogenic changes compared to control in k. l. Brain autopsy of the patient who died at age 18 years shows profound cerebellar atrophy (compared to control o), with dysmorphic Purkyně (also known as Purkinje) cells and loss of granule cells seen at higher magnification in m. compared to control p. n. Diffuse loss of motor neurons in the anterior horn of the spinal cord, compared to q. control with normal appearing spinal motor neurons.
Figure 2
Figure 2
EXOSC3 mutations in PCH1. a. Genomic structure of EXOSC3, with four exons in open boxes and mutations highlighted in magenta. circle- missense mutation; triangle- deletion mutation; star- splice site mutation. b. Alignment of orthologous sequences in human and other eukaryotic organisms, including vertebrate, insect, plant, and yeast, demonstrating that the mutated residues are conserved (highlighted in bold). c. Graphic representation of the locations of the mutated residues (highlighted in magenta) in EXOSC3, with conserved domains NT, S1, and KH (PDB code 2NN6).
Figure 3
Figure 3
Knockdown of exosc3 in zebrafish embryos disrupts normal development. a. Zebrafish embryos injected with exosc3-specific antisense morpholinos AUG (directed against the start codon) or SPL (directed against the splice donor site for exon 2), compared to nonspecific CTL. b. Whole-mount in situ hybridization in SPL morpholino-injected embryos in lateral view (inset- dorsal view, with rostral to the left) demonstrated diminished expression of dorsal hindbrain progenitor-specific marker atoh1a and cerebellar-specific marker pvalb7 compared to control. URL- upper rhombic lip; LRL-lower rhombic lip. *-distinct clusters of differentiated Purkinje cells in embryos 3dpf. c. Survival data from embryos 3dpf co-injected with 3 ng SPL and 240 pg of human EXOSC3 or zebrafish exosc3 mRNA vs. GFP mRNA as control, from three separate experiments. z-zebrafish; h-human; WT- wild type EXOSC3/exosc3; GA- mutant Gly31Ala in human or Gly20Ala in zebrafish; DA-mutant Asp132Ala in human or Asp102Ala in zebrafish; WR-mutant Trp238Arg in human or Trp208Arg in zebrafish. Embryos were classified as normal (blue) or abnormal (grey, which includes embryos that are mildly abnormal, severely abnormal, or dead). #, p<0.0001, two-tailed Pearson’s Chi-squared test.
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