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Loss of function mutations in RPL27 and RPS27 identified by whole‐exome sequencing in Diamond‐Blackfan anaemia
Author(s) -
Wang RuNan,
Yoshida Kenichi,
Toki Tsutomu,
Sawada Takafumi,
Uechi Tamayo,
Okuno Yusuke,
SatoOtsubo Aiko,
Kudo Kazuko,
Kamimaki Isamu,
Kanezaki Rika,
Shiraishi Yuichi,
Chiba Kenichi,
Tanaka Hiroko,
Terui Kiminori,
Sato Tomohiko,
Iribe Yuji,
Ohga Shouichi,
Kuramitsu Madoka,
Hamaguchi Isao,
Ohara Akira,
Hara Junichi,
Goi Kumiko,
Matsubara Kousaku,
Koike Kenichi,
Ishiguro Akira,
Okamoto Yasuhiro,
Watanabe Kenichiro,
Kanno Hitoshi,
Kojima Seiji,
Miyano Satoru,
Kenmochi Naoya,
Ogawa Seishi,
Ito Etsuro
Publication year - 2015
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/bjh.13229
Subject(s) - diamond–blackfan anemia , biology , exome sequencing , genetics , frameshift mutation , mutation , ribosomal protein , gene , gata1 , zebrafish , microbiology and biotechnology , ribosome , gene expression , rna
Summary 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 RPS 7 , RPS 10 , RPS 17 , RPS 19 , RPS 24 , RPS 26 , RPS 29, RPL 5 , RPL 11 , RPL 26 and RPL 35A as well as GATA 1 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 RPS 7 , RPL 26 , RPS 29 and GATA 1 . Here, we identified a de novo splicing error mutation in RPL 27 and frameshift deletion in RPS 27 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 RPL 3L , RPL 6 , RPL 7L1T , RPL 8 , RPL 13 , RPL 14 , RPL 18A and RPL 31 . 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.