Genetic and functional insights into CDA-I prevalence and pathogenesis.

Details

Serval ID
serval:BIB_2D6024C777F7
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Genetic and functional insights into CDA-I prevalence and pathogenesis.
Journal
Journal of medical genetics
Author(s)
Olijnik A.A., Roy NBA, Scott C., Marsh J.A., Brown J., Lauschke K., Ask K., Roberts N., Downes D.J., Brolih S., Johnson E., Xella B., Proven M., Hipkiss R., Ryan K., Frisk P., Mäkk J., Stattin E.M., Sadasivam N., McIlwaine L., Hill Q.A., Renella R., Hughes J.R., Gibbons R.J., Groth A., McHugh P.J., Higgs D.R., Buckle V.J., Babbs C.
ISSN
1468-6244 (Electronic)
ISSN-L
0022-2593
Publication state
Published
Issued date
09/06/2020
Peer-reviewed
Oui
Language
english
Notes
Publication types: Journal Article
Publication Status: aheadofprint
Abstract
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.
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.
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.
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.
Keywords
cell biology, clinical genetics, haematology (incl Blood transfusion), molecular genetics
Pubmed
Create date
14/06/2020 22:26
Last modification date
26/06/2020 5:21
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