{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T21:35:56Z","timestamp":1792445756222,"version":"4.5.0"},"reference-count":43,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2019,10,19]],"date-time":"2019-10-19T00:00:00Z","timestamp":1571443200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["MH111234"],"award-info":[{"award-number":["MH111234"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["NS084412"],"award-info":[{"award-number":["NS084412"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,3,13]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Missense mutations in the RNA exosome component exosome component 2 (EXOSC2), also known as ribosomal RNA-processing protein 4 (RRP4), were recently identified in two unrelated families with a novel syndrome known as Short stature, Hearing loss, Retinitis pigmentosa and distinctive Facies (SHRF, #OMIM 617763). Little is known about the mechanism of the SHRF pathogenesis. Here we have studied the effect of mutations in EXOSC2\/RRP4 in patient-derived lymphoblasts, clustered regularly interspaced short palindromic repeats (CRISPR)-generated mutant fetal keratinocytes and Drosophila. We determined that human EXOSC2 is an essential gene and that the pathogenic G198D mutation prevents binding to other RNA exosome components, resulting in protein and complex instability and altered expression and\/or activities of critical genes, including those in the autophagy pathway. In parallel, we generated multiple CRISPR knockouts of the fly rrp4 gene. Using these flies, as well as rrp4 mutants with Piggy Bac (PBac) transposon insertion in the 3\u2032UTR and RNAi flies, we determined that fly rrp4 was also essential, that fly rrp4 phenotypes could be rescued by wild-type human EXOSC2 but not the pathogenic form and that fly rrp4 is critical for eye development and maintenance, muscle ultrastructure and wing vein development. We found that overexpression of the transcription factor MITF was sufficient to rescue the small eye and adult lethal phenotypes caused by rrp4 inhibition. The autophagy genes ATG1 and ATG17, which are regulated by MITF, had similar effect. Pharmacological stimulation of autophagy with rapamycin also rescued the lethality caused by rrp4 inactivation. Our results implicate defective autophagy in SHRF pathogenesis and suggest therapeutic strategies.<\/jats:p>","DOI":"10.1093\/hmg\/ddz251","type":"journal-article","created":{"date-parts":[[2019,10,15]],"date-time":"2019-10-15T18:08:41Z","timestamp":1571162921000},"page":"541-553","source":"Crossref","is-referenced-by-count":30,"title":["Genetic and genomic studies of pathogenic EXOSC2 mutations in the newly described disease SHRF implicate the autophagy pathway in disease pathogenesis"],"prefix":"10.1093","volume":"29","author":[{"given":"Xue","family":"Yang","sequence":"first","affiliation":[{"name":"Department travellers of Pathology, Stanford School of Medicine, Stanford, CA 94305, USA"},{"name":"Department of Dermatology, Stanford School of Medicine, Stanford, CA 94305, USA"},{"name":"Program in Cancer Biology, Stanford School of Medicine, Stanford, CA 94305, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vafa","family":"Bayat","sequence":"first","affiliation":[{"name":"Department travellers of Pathology, Stanford School of Medicine, Stanford, CA 94305, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nataliya","family":"DiDonato","sequence":"first","affiliation":[{"name":"Institute for Clinical Genetics, TU Dresden, Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Dermatology, Stanford School of Medicine, Stanford, CA 94305, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Zarnegar","sequence":"first","affiliation":[{"name":"Department of Dermatology, Stanford School of Medicine, Stanford, CA 94305, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zurab","family":"Siprashvili","sequence":"first","affiliation":[{"name":"Department of Dermatology, Stanford School of Medicine, Stanford, CA 94305, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa","family":"Lopez-Pajares","sequence":"first","affiliation":[{"name":"Department of Dermatology, Stanford School of Medicine, Stanford, CA 94305, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Sun","sequence":"first","affiliation":[{"name":"Department of Genetics, Stanford School of Medicine, Stanford, CA 94305, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiying","family":"Tao","sequence":"first","affiliation":[{"name":"Department of Dermatology, Stanford School of Medicine, Stanford, CA 94305, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenjian","family":"Li","sequence":"first","affiliation":[{"name":"School of Life Sciences, Peking University, Beijing 100871, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Rump","sequence":"first","affiliation":[{"name":"Institute for Clinical Genetics, TU Dresden, Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Khavari","sequence":"first","affiliation":[{"name":"Department of Dermatology, Stanford School of Medicine, Stanford, CA 94305, USA"},{"name":"Program in Cancer Biology, Stanford School of Medicine, Stanford, CA 94305, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingwei","family":"Lu","sequence":"first","affiliation":[{"name":"Department travellers of Pathology, Stanford School of Medicine, Stanford, CA 94305, USA"},{"name":"Program in Cancer Biology, Stanford School of Medicine, Stanford, CA 94305, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2019,10,19]]},"reference":[{"key":"2020031301572257200_ref1","doi-asserted-by":"crossref","first-page":"154","DOI":"10.3389\/fmicb.2017.00154","article-title":"The structure and function of the gram-positive bacterial RNA degradosome","volume":"8","author":"Cho","year":"2017","journal-title":"Front. Microbiol."},{"key":"2020031301572257200_ref2","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1016\/S0092-8674(00)80432-8","article-title":"The exosome: a conserved eukaryotic RNA processing complex containing multiple 3\u2032--&gt;5\u2032 exoribonucleases","volume":"91","author":"Mitchell","year":"1997","journal-title":"Cell"},{"key":"2020031301572257200_ref3","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1101\/gad.10.4.502","article-title":"The 3\u2032 end of yeast 5.8S rRNA is generated by an exonuclease processing mechanism","volume":"10","author":"Mitchell","year":"1996","journal-title":"Genes Dev."},{"key":"2020031301572257200_ref4","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1016\/j.tibs.2013.06.013","article-title":"Threading the barrel of the RNA exosome","volume":"38","author":"Schneider","year":"2013","journal-title":"Trends Biochem. Sci."},{"key":"2020031301572257200_ref5","first-page":"8","article-title":"RNA surveillance by the nuclear RNA exosome: mechanisms and significance","volume":"4","author":"Ogami","year":"2018","journal-title":"Noncoding RNA"},{"key":"2020031301572257200_ref6","doi-asserted-by":"crossref","first-page":"4287","DOI":"10.1038\/ncomms5287","article-title":"EXOSC8 mutations alter mRNA metabolism and cause hypomyelination with spinal muscular atrophy and cerebellar hypoplasia","volume":"5","author":"Boczonadi","year":"2014","journal-title":"Nat. Commun."},{"key":"2020031301572257200_ref7","doi-asserted-by":"crossref","first-page":"858","DOI":"10.1016\/j.ajhg.2018.03.011","article-title":"Variants in EXOSC9 disrupt the RNA exosome and result in cerebellar atrophy with spinal motor neuronopathy","volume":"102","author":"Burns","year":"2018","journal-title":"Am. J. Hum. Genet."},{"key":"2020031301572257200_ref8","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/1750-1172-9-23","article-title":"EXOSC3 mutations in pontocerebellar hypoplasia type 1: novel mutations and genotype-phenotype correlations","volume":"9","author":"Eggens","year":"2014","journal-title":"Orphanet. J. Rare Dis."},{"key":"2020031301572257200_ref9","volume-title":"GeneReviews [Internet]","author":"Eggens","year":"1993-2019"},{"key":"2020031301572257200_ref10","first-page":"2985","article-title":"Altered RNA metabolism due to a homozygous RBM7 mutation in a patient with spinal motor neuropathy","volume":"25","author":"Giunta","year":"2016","journal-title":"Hum. Mol. Genet"},{"key":"2020031301572257200_ref11","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1136\/jmedgenet-2015-103511","article-title":"Mutations in EXOSC2 are associated with a novel syndrome characterised by retinitis pigmentosa, progressive hearing loss, premature ageing, short stature, mild intellectual disability and distinctive gestalt","volume":"53","author":"Di","year":"2016","journal-title":"J. Med. Genet"},{"key":"2020031301572257200_ref12","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.sbi.2014.01.011","article-title":"The eukaryotic RNA exosome","volume":"24","author":"Januszyk","year":"2014","journal-title":"Curr. Opin. Stru. Biol"},{"key":"2020031301572257200_ref13","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1146\/annurev-genet-110711-155456","article-title":"Probing mechanisms that underlie human neurodegenerative diseases in Drosophila","volume":"46","author":"Jaiswal","year":"2012","journal-title":"Annu. Rev. 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Genet."},{"key":"2020031301572257200_ref29","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/s12920-016-0170-0","article-title":"SOX5 is involved in balanced MITF regulation in human melanoma cells","volume":"9","author":"Kordass","year":"2016","journal-title":"BMC Med. Genom."},{"key":"2020031301572257200_ref30","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.17877","article-title":"Exosome complex orchestrates developmental signaling to balance proliferation and differentiation during erythropoiesis","volume":"5","author":"McIver","year":"2016","journal-title":"eLife"},{"key":"2020031301572257200_ref31","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1001\/archneurol.2010.351","article-title":"Resequencing of 29 candidate genes in patients with familial and sporadic amyotrophic lateral sclerosis","volume":"68","author":"Daoud","year":"2011","journal-title":"Arch. 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