Genetic and functional insights into CDA-I prevalence and pathogenesis

Aude Anais Olijnik, Noémi B.A. Roy, Caroline Scott, Joseph A. Marsh, Jill Brown, Karin Lauschke, Katrine Ask, Nigel Roberts, Damien J. Downes, Sanja Brolih, Errin Johnson, Barbara Xella, Melanie Proven, Ria Hipkiss, Kate Ryan, Per Frisk, Johan Mäkk, Eva Lena Maria Stattin, Nandini Sadasivam, Louisa McIlwaineQuentin A. Hill, Raffaele Renella, Jim R. Hughes, Richard J. Gibbons, Anja Groth, Peter J. McHugh, Douglas R. Higgs, Veronica J. Buckle, Christian Babbs*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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Abstract

Background: Congenital dyserythropoietic anaemia type I (CDA-I) is a hereditary anaemia caused by biallelic mutations in the widely expressed genes CDAN1 and C15orf41. Little is understood about either protein and it is unclear in which cellular pathways they participate. Methods: Genetic analysis of a cohort of patients with CDA-I identifies novel pathogenic variants in both known causative genes. We analyse the mutation distribution and the predicted structural positioning of amino acids affected in Codanin-1, the protein encoded by CDAN1. Using western blotting, immunoprecipitation and immunofluorescence, we determine the effect of particular mutations on both proteins and interrogate protein interaction, stability and subcellular localisation. Results: We identify six novel CDAN1 mutations and one novel mutation in C15orf41 and uncover evidence of further genetic heterogeneity in CDA-I. Additionally, population genetics suggests that CDA-I is more common than currently predicted. Mutations are enriched in six clusters in Codanin-1 and tend to affect buried residues. Many missense and in-frame mutations do not destabilise the entire protein. Rather C15orf41 relies on Codanin-1 for stability and both proteins, which are enriched in the nucleolus, interact to form an obligate complex in cells. Conclusion: Stability and interaction data suggest that C15orf41 may be the key determinant of CDA-I and offer insight into the mechanism underlying this disease. Both proteins share a common pathway likely to be present in a wide variety of cell types; however, nucleolar enrichment may provide a clue as to the erythroid specific nature of CDA-I. The surprisingly high predicted incidence of CDA-I suggests that better ascertainment would lead to improved patient care.

Original languageEnglish
JournalJournal of Medical Genetics
ISSN0022-2593
DOIs
Publication statusAccepted/In press - 2020

Keywords

  • cell biology
  • clinical genetics
  • haematology (incl Blood transfusion)
  • Molecular genetics

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