EXOSC8 mutations alter mRNA metabolism and cause hypomyelination with spinal muscular atrophy and cerebellar hypoplasia

Abstract

The exosome is a multi-protein complex, required for the degradation of AU-rich element (ARE) containing messenger RNAs (mRNAs). EXOSC8 is an essential protein of the exosome core, as its depletion causes a severe growth defect in yeast. Here we show that homozygous missense mutations in EXOSC8 cause progressive and lethal neurological disease in 22 infants from three independent pedigrees. Affected individuals have cerebellar and corpus callosum hypoplasia, abnormal myelination of the central nervous system or spinal motor neuron disease. Experimental downregulation of EXOSC8 in human oligodendroglia cells and in zebrafish induce a specific increase in ARE mRNAs encoding myelin proteins, showing that the imbalanced supply of myelin proteins causes the disruption of myelin, and explaining the clinical presentation. These findings show the central role of the exosomal pathway in neurodegenerative disease.

Insight into the RNA Exosome Complex Through Modeling Pontocerebellar Hypoplasia Type 1b Disease Mutations in Yeast

“…We next extended our analyses to assess whether these rrp40 variants affect the cytoplasmic functions of the RNA exosome. The rationale for examining cytoplasmic RNA exosome function is threefold: first, the cytoplasmic functions of the RNA exosome are nonessential, and thus distinct from those tested above (Jacobs Anderson and Parker 1998; Schaeffer et al 2010); second, residue substitutions in a different RNA exosome cap protein (Csl4/EXOSC1) inactivate cytoplasmic RNA exosome function without blocking the essential (nuclear) function ; and third, the hypothesis has been put forth that PCH1b and PCH1c are the result of a defect in cytoplasmic mRNA degradation by the RNA exosome (Boczonadi et al 2014).…”

“…We next extended our analyses to assess whether these rrp40 variants affect the cytoplasmic functions of the RNA exosome. The rationale for examining cytoplasmic RNA exosome function is threefold: first, the cytoplasmic functions of the RNA exosome are nonessential, and thus distinct from those tested above (Jacobs Anderson and Parker 1998; Schaeffer et al 2010); second, residue substitutions in a different RNA exosome cap protein (Csl4/EXOSC1) inactivate cytoplasmic RNA exosome function without blocking the essential (nuclear) function ; and third, the hypothesis has been put forth that PCH1b and PCH1c are the result of a defect in cytoplasmic mRNA degradation by the RNA exosome (Boczonadi et al 2014).To examine cytoplasmic exosome function in rrp40 mutants, we employed a his3-nonstop reporter assay that exploits the observation that the budding yeast cytoplasmic RNA exosome is required for the degradation of mRNAs that lack stop codons . In cells with functional cytoplasmic exosome, the his3-nonstop mRNA reporter, which encodes the His3 protein and lacks stop codons, is degraded, no histidine is made, and the cells cannot grow on media lacking histidine.…”

“…In addition, mutations in the DIS3 catalytic subunit gene have been implicated in multiple myeloma (Chapman et al 2011;Tomecki et al 2013;Robinson et al 2015). Recently, mutations in genes encoding structural exosome subunits have been linked to neurological diseases Boczonadi et al 2014;. Mutations in the gene encoding the RNA exosome cap subunit, EXOSC3 (Figure 1, B and C), have been linked to pontocerebellar hypoplasia type 1b (PCH1b) ).…”

“…Finally, EXOSC3 changes could impair functions of EXOSC3 that are independent of the RNA exosome. This last mechanism seems less likely, as mutations in another exosome subunit gene, EXOSC8, cause PCH1c disease (Boczonadi et al 2014).To begin to address the molecular defects that underlie PCH1b disease, we have generated and analyzed amino acid substitutions in the budding yeast ortholog of EXOSC3, Rrp40, corresponding to substitutions in PCH1b patients. Unlike most rrp40 variants analyzed, which do not exhibit any discernable phenotypes in yeast, the rrp40-W195R variant, corresponding to EXOSC3-W238R in PCH1b, affects cell growth and RNA exosome function as the sole cellular copy.…”

Mutations in SNX14 Cause a Distinctive Autosomal-Recessive Cerebellar Ataxia and Intellectual Disability Syndrome

“…Several different cellular mechanisms have been implicated including mutations in SIL1, coding for an endoplasmic reticulum resident cochaperone, which cause Marinesco-Sjogren syndrome (MSS [MIM 248800]); 1 sialic acid disorders such as Salla disease (MIM 604369); 2 disorders of peroxisome biogenesis in atypical Refsum disease (MIM 614879); 3 congenital disorders of glycosylation, especially type 1a caused by mutations in PMM2 (MIM 212065); 4 and the X-linked ID-small cerebellum syndrome caused by mutations in OPHN1 (MIM 300486), a RhoGTPase-activating protein (GAP). 5 Related phenotypes include the group designated as pontocerebellar hypoplasias, 6 within which causal mutations have been found in a number of genes involved in tRNA biogenesis (including RARS2 11,12 and another (CHMP1A [MIM 614961]), with a dual role in protein sorting at the endosome and chromatin modification at the nucleus. 13 Other cellular processes include synaptic and cell junction function (CASK [MIM 300749]), 14 cell cycle progression, and cell division (the serine-threonine kinase VRK1 [MIM 607596]).…”