Genetic and functional insights into CDA-I prevalence and pathogenesis

Congenital Dyserythropoietic Anaemia type I (CDA-I) is a hereditary anaemia caused by biallelic mutations in the widely expressed genes CDAN1 (encoding Codanin-1) or C15orf41. In this study, we analyse a cohort of CDA-I patients and identify novel pathogenic variants. We predict CDA-I is five times more common than currently thought. Functional assays show Codanin-1 and C15orf41 interact and depletion of Codanin-1 results in reduction of C15orf41 level. Interestingly these two proteins are enriched in the nucleoli of erythroid cells. We also identify hotspots of mutations in CDAN1, which indicate domains involved in CDA-I pathogenesis. Western-Blot analysis of erythroblasts cultured from four CDA-I patients shows there is no overall destabilisation of the proteins. This work provides further insights into the erythroid-specific nature of the disease and supports clinicians by improving CDA-I diagnostic range. (By Dr. Christian Babbs, https://jmg.bmj.com/content/early/2020/06/09/jmedgenet-2020-106880 )

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