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

Haematologica. 2013 Sep;98(9):1383-7. doi: 10.3324/haematol.2013.089490. Epub 2013 May 28.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anemia, Dyserythropoietic, Congenital / diagnosis*
  • Anemia, Dyserythropoietic, Congenital / genetics*
  • Endonucleases / chemistry
  • Endonucleases / genetics
  • Female
  • Glycoproteins / chemistry
  • Glycoproteins / genetics*
  • Homozygote*
  • Humans
  • Male
  • Mutation, Missense / genetics*
  • Nuclear Proteins
  • Pedigree
  • Predictive Value of Tests
  • Protein Structure, Secondary
  • Protein Structure, Tertiary

Substances

  • CDAN1 protein, human
  • Glycoproteins
  • Nuclear Proteins
  • Endonucleases