title: DNAJC21 Mutations Link a Cancer-Prone Bone Marrow Failure Syndrome to Corruption in 60S Ribosome Subunit Maturation.
abstract: A substantial number of individuals with bone marrow failure (BMF) present with one or more extra-hematopoietic abnormality. This suggests a constitutional or inherited basis, and yet many of them do not fit the diagnostic criteria of the known BMF syndromes. Through exome sequencing, we have now identified a subgroup of these individuals, defined by germline biallelic mutations in DNAJC21 (DNAJ homolog subfamily C member 21). They present with global BMF, and one individual developed a hematological cancer (acute myeloid leukemia) in childhood. We show that the encoded protein associates with rRNA and plays a highly conserved role in the maturation of the 60S ribosomal subunit. Lymphoblastoid cells obtained from an affected individual exhibit increased sensitivity to the transcriptional inhibitor actinomycin D and reduced amounts of rRNA. Characterization of mutations revealed impairment in interactions with cofactors (PA2G4, HSPA8, and ZNF622) involved in 60S maturation. DNAJC21 deficiency resulted in cytoplasmic accumulation of the 60S nuclear export factor PA2G4, aberrant ribosome profiles, and increased cell death. Collectively, these findings demonstrate that mutations in DNAJC21 cause a cancer-prone BMF syndrome due to corruption of early nuclear rRNA biogenesis and late cytoplasmic maturation of the 60S subunit.
authors.affiliation: Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
authors.forename: Hemanth
authors.initials: H
authors.lastname: Tummala
authors.affiliation: Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Walne
authors.affiliation: Clinical and Laboratory Haematology, Birmingham Children's Hospital, Birmingham B4 6NH, UK.
authors.forename: Mike
authors.initials: M
authors.lastname: Williams
authors.affiliation: Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Bockett
authors.affiliation: Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Collopy
authors.affiliation: Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
authors.forename: Shirleny
authors.initials: S
authors.lastname: Cardoso
authors.affiliation: Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
authors.forename: Alicia
authors.initials: A
authors.lastname: Ellison
authors.affiliation: Blood and Marrow Transplant Unit, Royal Manchester Children's Hospital, Manchester M13 9WL, UK.
authors.forename: Rob
authors.initials: R
authors.lastname: Wynn
authors.affiliation: Pediatric Hematology, Hôpital Robert-Debré, APHP, Paris 75019, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Leblanc
authors.affiliation: Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
authors.forename: Jude
authors.initials: J
authors.lastname: Fitzgibbon
authors.affiliation: Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
authors.forename: David P
authors.initials: DP
authors.lastname: Kelsell
authors.affiliation: Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: van Heel
authors.affiliation: UCL Cancer Institute, 72 Huntley Street, London WC1E 6DD, UK.
authors.forename: Elspeth
authors.initials: E
authors.lastname: Payne
authors.affiliation: UCL Genetics Institute, Gower Place, London WC1E 6DD, UK.
authors.forename: Vincent
authors.initials: V
authors.lastname: Plagnol
authors.affiliation: Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
authors.forename: Inderjeet
authors.initials: I
authors.lastname: Dokal
authors.affiliation: Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK. Electronic address: t.vulliamy@qmul.ac.uk.
authors.forename: Tom
authors.initials: T
authors.lastname: Vulliamy
mesh_terms: D000595:Amino Acid Sequence; D000741:Anemia, Aplastic / Q000150:complications* / Q000235:genetics*; D001855:Bone Marrow Diseases / Q000150:complications* / Q000235:genetics*; D000080983:Bone Marrow Failure Disorders; D049109:Cell Proliferation; D048430:Cell Shape; D002648:Child; D002675:Child, Preschool; D005260:Female; D050956:HSP40 Heat-Shock Proteins / Q000737:chemistry / Q000235:genetics*; D006457:Hemoglobinuria, Paroxysmal / Q000150:complications* / Q000235:genetics*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000150:complications / Q000235:genetics; D008297:Male; D009154:Mutation / Q000235:genetics*; D009369:Neoplasms / Q000150:complications* / Q000235:genetics*; D011485:Protein Binding; D012335:RNA, Ribosomal / Q000096:biosynthesis; D054683:Ribosome Subunits, Large, Eukaryotic / Q000378:metabolism* / Q000473:pathology*
chemical_list: C000618996:DNAJC21 protein, human; D050956:HSP40 Heat-Shock Proteins; D012335:RNA, Ribosomal