Mutations in<i>EXOSC2</i>are associated with a novel syndrome characterised by retinitis pigmentosa, progressive hearing loss, premature ageing, short stature, mild intellectual disability and distinctive gestalt

Donato, Nataliya Di; Neuhann, Teresa; Kahlert, Anne Karin; Klink, Barbara; Hackmann, Karl; Neuhann, Irmingard M.; Novotná, Barbora; Schallner, Jens; Krause, C.; Glass, Ian A.; Parnell, Shawn E.; Benet‐Pagès, Anna; Nissen, Anke M.; Berger, Wolfgang; Altmüller, Janine; Thiele, Holger; Weber, Bernhard H. F.; Schröck, Evelin; Dobyns, William B.; Bier, August; Rump, Andreas

doi:10.1136/jmedgenet-2015-103511

Cited by 76 publications

(127 citation statements)

References 18 publications

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“…Conversely, seizures and spasticity, which have been reported in families 1 and 2, respectively, were not observed in the German patients. Minor anomalies in faces such as prominent forehead and broad nasal tip have been found in both German and Iranian patients . As we found the novel variant c.673‐1G > T in intron 7 of EXOSC2 in two unrelated families located in two different provinces which share a long border, it might be an implication of a founder effect in the Iranian population.…”

Section: Discussionsupporting

confidence: 50%

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Identification of disease‐causing variants in the EXOSC gene family underlying autosomal recessive intellectual disability in Iranian families

et al. 2019

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Neurodevelopmental delay and intellectual disability (ID) can arise from numerous genetic defects. To date, variants in the EXOSC gene family have been associated with such disorders. Using next‐generation sequencing (NGS), known and novel variants in this gene family causing autosomal recessive ID (ARID) have been identified in five Iranian families. By collecting clinical information on these families and comparing their phenotypes with previously reported patients, we further describe the clinical variability of ARID resulting from alterations in the EXOSC gene family, and emphasize the role of RNA processing dysregulation in ARID.

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Section: Discussionsupporting

confidence: 50%

“…The EXOSC gene family is involved in the RNA exosome complex which is evolutionarily conserved with catalytic and structural subunits degrading and/or processing a wide variety of RNA species . Mutations in RNA exosome genes have recently been linked to distinct syndromes with tissue‐specific disorders …”

Section: Introductionmentioning

confidence: 99%

Identification of disease‐causing variants in the EXOSC gene family underlying autosomal recessive intellectual disability in Iranian families

et al. 2019

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“…In the last 2 years several other studies indicated that mutations in EXOSC3 result in a more variable clinical presentation, suggesting that exosome complex dysfunction is a major cause of severe childhood onset complex inherited neurological disorders. More recently, also mutations in EXOSC2 found in two unrelated German families were shown to cause neurodevelopmental defects such as mild cerebellar atrophy and cerebellar hypoplasia, diffuse dysmyelination, hearing loss, mild intellectual disability, facial anomalies and premature ageing (20). …”

Section: Introductionmentioning

confidence: 99%

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

Giunta

Edvardson

et al. 2016

Hum. Mol. Genet.

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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.

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“…These molecular functions are best defined in yeast, but many are conserved in human cells (Staals and Pruijn, 2011). In human patients, different mutations that affect RNA exosome activity are associated with distinct human diseases: multiple myeloma (Weissbach et al, 2015), pontocerebellar hypoplasia (Boczonadi et al, 2014; Wan et al, 2012), trichohepatoenteric syndrome (Fabre et al, 2012; Hartley et al, 2010), and most recently, a distinct disorder that has not yet been named (Di Donato et al, 2016). A thorough investigation of the structure and function of the RNA exosome is essential to understand how the RNA exosome carries out all of these functions, and how RNA exosome defects cause these very diverse diseases.…”

Section: Introductionmentioning

confidence: 99%

The RNA Exosome Channeling and Direct Access Conformations Have Distinct In Vivo Functions

Han

Hoof

2016

Cell Reports

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The RNA exosome is a 3′-5′ ribonuclease complex that is composed of nine core subunits and an essential catalytic subunit, Rrp44. Two distinct conformations of Rrp44 were revealed in previous structural studies, suggesting that Rrp44 may change its conformation to exert its function. In the channeling conformation (Rrp44ch) RNA accesses the active site after traversing the central channel of the RNA exosome, while in the other conformation (Rrp44da) RNA gains direct access to the active site. Here, we show that the Rrp44da-exosome is important for nuclear function of the RNA exosome. Defects caused by disrupting the direct access conformation are distinct from those caused by channel-occluding mutations, indicating specific functions for each conformation. Our genetic analyses provide in vivo evidence that the RNA exosome employs a direct-access route to recruit specific substrates, indicating that the RNA exosome uses alternative conformations to act on different RNA substrates.

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Mutations inEXOSC2are associated with a novel syndrome characterised by retinitis pigmentosa, progressive hearing loss, premature ageing, short stature, mild intellectual disability and distinctive gestalt

Abstract: We report a novel condition that is probably caused by altered RNA exosome function and expands the spectrum of clinical consequences of impaired RNA metabolism.

Cited by 76 publications

References 18 publications

Identification of disease‐causing variants in the EXOSC gene family underlying autosomal recessive intellectual disability in Iranian families

Identification of disease‐causing variants in the EXOSC gene family underlying autosomal recessive intellectual disability in Iranian families

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

The RNA Exosome Channeling and Direct Access Conformations Have Distinct In Vivo Functions

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