Homozygous mutations in a predicted endonuclease are a novel cause of congenital dyserythropoietic anemia type I

WGS500 Consortium, Christian Babbs, Nigel A Roberts, Luis Sanchez-Pulido, Simon J McGowan, Momin R Ahmed, Jill M Brown, Mohamed A Sabry, David R Bentley, Gil A McVean, Peter Donnelly, Opher Gileadi, Chris P Ponting, Douglas R Higgs, Veronica J Buckle

Research output: Contribution to journalArticlepeer-review

Abstract

The congenital dyserythropoietic anemias are a heterogeneous group of rare disorders primarily affecting erythropoiesis with characteristic morphological abnormalities and a block in erythroid maturation. Mutations in the CDAN1 gene, which encodes Codanin-1, underlie the majority of congenital dyserythropoietic anemia type I cases. However, no likely pathogenic CDAN1 mutation has been detected in approximately 20% of cases, suggesting the presence of at least one other locus. We used whole genome sequencing and segregation analysis to identify a homozygous T to A transversion (c.533T>A), predicted to lead to a p.L178Q missense substitution in C15ORF41, a gene of unknown function, in a consanguineous pedigree of Middle-Eastern origin. Sequencing C15ORF41 in other CDAN1 mutation-negative congenital dyserythropoietic anemia type I pedigrees identified a homozygous transition (c.281A>G), predicted to lead to a p.Y94C substitution, in two further pedigrees of SouthEast Asian origin. The haplotype surrounding the c.281A>G change suggests a founder effect for this mutation in Pakistan. Detailed sequence similarity searches indicate that C15ORF41 encodes a novel restriction endonuclease that is a member of the Holliday junction resolvase family of proteins.

Original languageEnglish
Pages (from-to)1383-7
Number of pages5
JournalHaematologica
Volume98
Issue number9
DOIs
Publication statusPublished - Sep 2013

Keywords

  • Anemia, Dyserythropoietic, Congenital
  • Endonucleases
  • Female
  • Glycoproteins
  • Homozygote
  • Humans
  • Male
  • Mutation, Missense
  • Pedigree
  • Predictive Value of Tests
  • Protein Structure, Secondary
  • Protein Structure, Tertiary

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