Altered RNA metabolism due to a homozygousRBM7mutation in a patient with spinal motor neuropathy

Abstract

The exosome complex is the most important RNA processing machinery within the cell. Mutations in its subunits EXOSC8 and EXOSC3 cause pontocerebellar hypoplasia, spinal muscular atrophy (SMA) and central nervous system demyelination. We present a patient with SMA-like phenotype carrying a homozygous mutation in RBM7—a subunit of the nuclear exosome targeting (NEXT) complex—which is known to bind and carry specific subtypes of coding and non-coding RNAs to the exosome. The NEXT complex with other protein complexes is responsible for the substrate specificity of the exosome. We performed RNA-sequencing (RNA-seq) analysis on primary fibroblasts of patients with mutations in EXOSC8 and RBM7 and gene knock-down experiments using zebrafish as a model system. RNA-seq analysis identified significantly altered expression of 62 transcripts shared by the two patient cell lines. Knock-down of rbm7, exosc8 and exosc3 in zebrafish showed a common pattern of defects in motor neurons and cerebellum. Our data indicate that impaired RNA metabolism may underlie the clinical phenotype by fine tuning gene expression which is essential for correct neuronal differentiation.

Tricho-Hepato-Enteric Syndrome mutation update: Mutations spectrum ofTTC37andSKIV2L, clinical analysis and future prospects

“…Up to now, mutations in three other exosome proteins have been shown to cause monogenic diseases: EXOSC2, EXOSC3, and EXOSC8, but only sparse characteristics are shared with THE, reinforcing the hypothesis of independent functions of the SKI complex (Di Donato et al., ; Rudnik‐Schöneborn et al., ; Wan et al., ). Another cofactor (RBM7) of the nuclear exosome targeting complex (NEXT) has recently been reported to be involved in a human disease, also with neural damages (SMA‐like phenotype) (Giunta et al., ). It is likely that these neurological diseases are rather due to the core function of the exosome in the nucleus compartment.…”

The RNA exosome and RNA exosome-linked disease

“…Notably, the nuclear Mtr4/hMTR4/SKIV2L2 cofactor and cytoplasmic Ski2/SKIV2L cofactor, both DExH box ATPdependent RNA helicases, play pivotal roles in remodeling RNA substrates for the RNA exosome (Johnson and Jackson 2013;Schneider and Tollervey 2013). Thus far, mutations in genes encoding components of the NEXT complex (RBM7) and the Ski complex (SKIV2L and TTC37) have been linked to human disease (Hartley et al 2010;Fabre et al 2012;Giunta et al 2016).…”

The RNA Exosome Syncs IAV-RNAPII Transcription to Promote Viral Ribogenesis and Infectivity

“…Moreover, recent reports have identified novel neurodegeneration-causing mutations in other components of the RNA exosome (EXOSC8) and its nuclear cofactor (RBM7) (Boczonadi et al, 2014; Giunta et al, 2016). …”

“…Human congenital mutations in many exosome subunits cause impaired exosome activity and are associated with cognitive impairment and neurodegeneration (Wan et al, 2012; Rudnik-Schoneborn et al, 2013; Boczonadi et al, 2014; Giunta et al, 2016). We analyzed the relationship between exosome mutations and the viral life cycle, and show that suppression of viral replication occurs in patient-derived cells, suggesting that exosome hypomorphs might display altered susceptibility to IAV infection.…”