Genetic and functional insights into CDA-I prevalence and pathogenesis
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Genetic and functional insights into CDA-I prevalence and pathogenesis. / Olijnik, Aude-Anais; Roy, Noémi B A; Scott, Caroline; Marsh, Joseph A; Brown, Jill; Lauschke, Karin; Ask, Katrine; Roberts, Nigel; Downes, Damien J; Brolih, Sanja; Johnson, Errin; Xella, Barbara; Proven, Melanie; Hipkiss, Ria; Ryan, Kate; Frisk, Per; Mäkk, Johan; Stattin, Eva-Lena Maria; Sadasivam, Nandini; McIlwaine, Louisa; Hill, Quentin A; Renella, Raffaele; Hughes, Jim R; Gibbons, Richard J; Groth, Anja; McHugh, Peter J; Higgs, Douglas R; Buckle, Veronica J; Babbs, Christian.
In: Journal of Medical Genetics, Vol. 58, 2021, p. 185-195.Research output: Contribution to journal › Journal article › Research › peer-review
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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 -
ID: 243077431