title: Loss of function mutations in RPL27 and RPS27 identified by whole-exome sequencing in Diamond-Blackfan anaemia.
abstract: Diamond-Blackfan anaemia is a congenital bone marrow failure syndrome that is characterized by red blood cell aplasia. The disease has been associated with mutations or large deletions in 11 ribosomal protein genes including RPS7, RPS10, RPS17, RPS19, RPS24, RPS26, RPS29, RPL5, RPL11, RPL26 and RPL35A as well as GATA1 in more than 50% of patients. However, the molecular aetiology of many Diamond-Blackfan anaemia cases remains to be uncovered. To identify new mutations responsible for Diamond-Blackfan anaemia, we performed whole-exome sequencing analysis of 48 patients with no documented mutations/deletions involving known Diamond-Blackfan anaemia genes except for RPS7, RPL26, RPS29 and GATA1. Here, we identified a de novo splicing error mutation in RPL27 and frameshift deletion in RPS27 in sporadic patients with Diamond-Blackfan anaemia. In vitro knockdown of gene expression disturbed pre-ribosomal RNA processing. Zebrafish models of rpl27 and rps27 mutations showed impairments of erythrocyte production and tail and/or brain development. Additional novel mutations were found in eight patients, including RPL3L, RPL6, RPL7L1T, RPL8, RPL13, RPL14, RPL18A and RPL31. In conclusion, we identified novel germline mutations of two ribosomal protein genes responsible for Diamond-Blackfan anaemia, further confirming the concept that mutations in ribosomal protein genes lead to Diamond-Blackfan anaemia.
authors.affiliation: Department of Paediatrics, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: RuNan
authors.initials: R
authors.lastname: Wang
authors.forename: Kenichi
authors.initials: K
authors.lastname: Yoshida
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Toki
authors.forename: Takafumi
authors.initials: T
authors.lastname: Sawada
authors.forename: Tamayo
authors.initials: T
authors.lastname: Uechi
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Okuno
authors.forename: Aiko
authors.initials: A
authors.lastname: Sato-Otsubo
authors.forename: Kazuko
authors.initials: K
authors.lastname: Kudo
authors.forename: Isamu
authors.initials: I
authors.lastname: Kamimaki
authors.forename: Rika
authors.initials: R
authors.lastname: Kanezaki
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Shiraishi
authors.forename: Kenichi
authors.initials: K
authors.lastname: Chiba
authors.forename: Hiroko
authors.initials: H
authors.lastname: Tanaka
authors.forename: Kiminori
authors.initials: K
authors.lastname: Terui
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Sato
authors.forename: Yuji
authors.initials: Y
authors.lastname: Iribe
authors.forename: Shouichi
authors.initials: S
authors.lastname: Ohga
authors.forename: Madoka
authors.initials: M
authors.lastname: Kuramitsu
authors.forename: Isao
authors.initials: I
authors.lastname: Hamaguchi
authors.forename: Akira
authors.initials: A
authors.lastname: Ohara
authors.forename: Junichi
authors.initials: J
authors.lastname: Hara
authors.forename: Kumiko
authors.initials: K
authors.lastname: Goi
authors.forename: Kousaku
authors.initials: K
authors.lastname: Matsubara
authors.forename: Kenichi
authors.initials: K
authors.lastname: Koike
authors.forename: Akira
authors.initials: A
authors.lastname: Ishiguro
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Okamoto
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Watanabe
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kanno
authors.forename: Seiji
authors.initials: S
authors.lastname: Kojima
authors.forename: Satoru
authors.initials: S
authors.lastname: Miyano
authors.forename: Naoya
authors.initials: N
authors.lastname: Kenmochi
authors.forename: Seishi
authors.initials: S
authors.lastname: Ogawa
authors.forename: Etsuro
authors.initials: E
authors.lastname: Ito
mesh_terms: D029503:Anemia, Diamond-Blackfan / Q000235:genetics* / Q000503:physiopathology; D000818:Animals; D002675:Child, Preschool; D004252:DNA Mutational Analysis / Q000379:methods; D004920:Erythropoiesis / Q000235:genetics; D059472:Exome / Q000235:genetics; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008667:Metalloproteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D010375:Pedigree; D012335:RNA, Ribosomal / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics*; D012269:Ribosomal Proteins / Q000235:genetics*; D015027:Zebrafish
chemical_list: D008667:Metalloproteins; D009687:Nuclear Proteins; D012335:RNA, Ribosomal; D016601:RNA-Binding Proteins; C083686:RPS27 protein, human; D012269:Ribosomal Proteins; C034661:ribosomal proteins L27
keywords: Diamond-Blackfan; bone marrow failure; childhood; erythropoiesis; genetic analysis