TY - JOUR

T1 - Genetic and functional insights into CDA-I prevalence and pathogenesis

AU - Olijnik, Aude-Anais

AU - Roy, Noémi B A

AU - Scott, Caroline

AU - Marsh, Joseph A

AU - Brown, Jill

AU - Lauschke, Karin

AU - Ask, Katrine

AU - Roberts, Nigel

AU - Downes, Damien J

AU - Brolih, Sanja

AU - Johnson, Errin

AU - Xella, Barbara

AU - Proven, Melanie

AU - Hipkiss, Ria

AU - Ryan, Kate

AU - Frisk, Per

AU - Mäkk, Johan

AU - Stattin, Eva-Lena Maria

AU - Sadasivam, Nandini

AU - McIlwaine, Louisa

AU - Hill, Quentin A

AU - Renella, Raffaele

AU - Hughes, Jim R

AU - Gibbons, Richard J

AU - Groth, Anja

AU - McHugh, Peter J

AU - Higgs, Douglas R

AU - Buckle, Veronica J

AU - Babbs, Christian

PY - 2021

Y1 - 2021

N2 - 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.

AB - 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.

U2 - 10.1136/jmedgenet-2020-106880

DO - 10.1136/jmedgenet-2020-106880

M3 - Journal article

C2 - 32518175

VL - 58

SP - 185

EP - 195

JO - Journal of Medical Genetics

JF - Journal of Medical Genetics

SN - 0022-2593

ER -