2. Academic Validation
  3. DNAJC21 Mutations Link a Cancer-Prone Bone Marrow Failure Syndrome to Corruption in 60S Ribosome Subunit Maturation

DNAJC21 Mutations Link a Cancer-Prone Bone Marrow Failure Syndrome to Corruption in 60S Ribosome Subunit Maturation

  • Am J Hum Genet. 2016 Jul 7;99(1):115-24. doi: 10.1016/j.ajhg.2016.05.002.
Hemanth Tummala 1,  Amanda J Walne 1,  Mike Williams 2,  Nicholas Bockett 1,  Laura Collopy 1,  Shirleny Cardoso 1,  Alicia Ellison 1,  Rob Wynn 3,  Thierry Leblanc 4,  Jude Fitzgibbon 5,  David P Kelsell 6,  David A van Heel 1,  Elspeth Payne 7,  Vincent Plagnol 8,  Inderjeet Dokal 1,  Tom Vulliamy 9
Affiliations

Affiliations

  • 1 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.
  • 2 Clinical and Laboratory Haematology, Birmingham Children's Hospital, Birmingham B4 6NH, UK.
  • 3 Blood and Marrow Transplant Unit, Royal Manchester Children's Hospital, Manchester M13 9WL, UK.
  • 4 Pediatric Hematology, Hôpital Robert-Debré, APHP, Paris 75019, France.
  • 5 Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
  • 6 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.
  • 7 UCL Cancer Institute, 72 Huntley Street, London WC1E 6DD, UK.
  • 8 UCL Genetics Institute, Gower Place, London WC1E 6DD, UK.
  • 9 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: [email protected].
PMID: 27346687 DOI: 10.1016/j.ajhg.2016.05.002
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.

Figures