title: Homozygous mutations in a predicted endonuclease are a novel cause of congenital dyserythropoietic anemia type I.
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.
authors.affiliation: Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
authors.forename: Christian
authors.initials: C
authors.lastname: Babbs
authors.forename: Nigel A
authors.initials: NA
authors.lastname: Roberts
authors.forename: Luis
authors.initials: L
authors.lastname: Sanchez-Pulido
authors.forename: Simon J
authors.initials: SJ
authors.lastname: McGowan
authors.forename: Momin R
authors.initials: MR
authors.lastname: Ahmed
authors.forename: Jill M
authors.initials: JM
authors.lastname: Brown
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Sabry
authors.forename: David R
authors.initials: DR
authors.lastname: Bentley
authors.forename: Gil A
authors.initials: GA
authors.lastname: McVean
authors.forename: Peter
authors.initials: P
authors.lastname: Donnelly
authors.forename: Opher
authors.initials: O
authors.lastname: Gileadi
authors.forename: Chris P
authors.initials: CP
authors.lastname: Ponting
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Higgs
authors.forename: Veronica J
authors.initials: VJ
authors.lastname: Buckle
mesh_terms: D000742:Anemia, Dyserythropoietic, Congenital / Q000175:diagnosis* / Q000235:genetics*; D004720:Endonucleases / Q000737:chemistry / Q000235:genetics; D005260:Female; D006023:Glycoproteins / Q000737:chemistry / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008297:Male; D020125:Mutation, Missense / Q000235:genetics*; D009687:Nuclear Proteins; D010375:Pedigree; D011237:Predictive Value of Tests; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
chemical_list: C470477:CDAN1 protein, human; D006023:Glycoproteins; D009687:Nuclear Proteins; D004720:Endonucleases