umu.sePublications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Congenital dyserythropoietic anemia type III (CDA III) is caused by a mutation in kinesin family member, KIF23.
Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
Show others and affiliations
2013 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020Article in journal (Refereed) Published
Abstract [en]

Haplotype analysis and targeted next-generation resequencing allowed us to identify a mutation in the KIF23 gene and to show its association with an autosomal dominant form of congenital dyserythropoietic anemia type III (CDA III). The region at 15q23 where CDA III was mapped in a large Swedish family was targeted by array-based sequence capture in a female diagnosed with CDA III and her healthy sister. Prioritization of all detected sequence changes revealed 10 variants unique for the CDA III patient. Among those variants, a novel mutation c.2747C>G (p.P916R) was found in KIF23, which encodes mitotic kinesin-like protein 1 (MKLP1). This variant segregates with CDA III in the Swedish and American families but was not found in 356 control individuals. RNA expression of the 2 known splice isoforms of KIF23 as well as a novel one lacking the exons 17 and 18 was detected in a broad range of human tissues. RNA interference-based knock-down and rescue experiments demonstrated that the p.P916R mutation causes cytokinesis failure in HeLa cells, consistent with appearance of large multinucleated erythroblasts in CDA III patients. We conclude that CDA III is caused by a mutation in KIF23/MKLP1, a conserved mitotic kinesin crucial for cytokinesis.

Place, publisher, year, edition, pages
2013.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:umu:diva-70201DOI: 10.1182/blood-2012-10-461392ISI: 000321895700025PubMedID: 23570799OAI: oai:DiVA.org:umu-70201DiVA: diva2:620098
Available from: 2013-05-07 Created: 2013-05-07 Last updated: 2017-12-06Bibliographically approved
In thesis
1. Congenital Dyserythropoietic Anemia type III (CDA III): diagnostics, genetics and morbidity
Open this publication in new window or tab >>Congenital Dyserythropoietic Anemia type III (CDA III): diagnostics, genetics and morbidity
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The Congenital Dyserythropoietic Anemias (CDA) are rare hereditary hemolytic disorders with large bi- to multi-nucleated erythroblasts in the bone marrow. Hemolysis is negative in a direct antiglobulin test (DAT). Based on morphology and clinical picture, three major forms of CDAs, type I, II, and III have been defined. CDA III, dominantly inherited, constitutes the rarest type with a majority of cases belonging to a family in Västerbotten, Sweden. The genetic background of CDA I and CDA II has been linked to mutations in CDAN1 and SEC23B respectively. The mutation of CDA III has been linked to 15q22 in earlier studies.

In this project we have defined the causative genetic lesion in two families with CDA III. The novel mutation KIF23 c.2747C>G (p.P916R) was shown to segregate with CDA III in the Swedish and American CDA III families and was absent in 356 healthy controls. KIF23 encodes mitotic kinesin-like protein 1 (MKLP1), which plays a central role in the last step of cytokinesis. RNAi-based knock-down and rescue experiments demonstrated that the p.P916R mutation causes cytokinesis failure in HeLa cells, resulting in increasing number of bi-nuclear cells, consistent with appearance of large multinucleated erythroblasts in CDA III patients. We conclude that CDA III is caused by a mutation in KIF23, encoding MKLP1, a conserved mitotic kinesin crucial for cytokinesis.

Flow cytometry with eosin-5´-maleimide (EMA), anti-CD55 and anti-CD59 is commonly used when investigating non-autoimmune hemolytic anemias. Reduced fluorescence of EMA, typically detected in hereditary spherocytosis, is also seen in CDA II, while reduction of CD55 and CD59 characterizes paroxysmal nocturnal hemoglobinuria (PNH). We studied the flow cytometric profile of EMA, CD55, and CD59 on erythrocytes in CDA III. We found no abnormality of the erythrocyte membrane in CDA III and concluded that standard flow cytometry cannot be used to discriminate between CDA III and normal controls.

In CDA I and CDA II a majority of patients, including those who are not transfusion dependent, suffer from iron overload, which, according to earlier studies, is not the case in CDA III. We found that individuals of the Västerbotten CDA III family carry mutations in the hemochromatosis (HFE) gene. Three CDA III patients with heterozygous or compound HFE mutations need treatment with phlebotomy due to iron overload. One of them carries heterozygous H63D mutation, which is not reported to lead to iron overload by itself in otherwise healthy individuals. We propose that molecular genetic testing of the HFE gene is indicated in all patients with CDA, including CDA III.

Place, publisher, year, edition, pages
Umeå: print och media, 2016. 54 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1784
Keyword
congenital dyserythropoietic anemia, KIF23, hereditary hemochromatosis, iron overload, flow cytometry
National Category
Hematology
Identifiers
urn:nbn:se:umu:diva-117454 (URN)978-91-7601-424-0 (ISBN)
Public defence
2016-04-22, E04, By 6E, 901 85, Norrlands Universitets sjukhus, Umeå, 19:35 (Swedish)
Opponent
Supervisors
Available from: 2016-04-15 Created: 2016-02-29 Last updated: 2016-04-22Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full textPubMed

Authority records BETA

Liljeholm, MariaNorberg, AnnaSandström, HerbertWahlin, AndersGolovleva, Irina

Search in DiVA

By author/editor
Liljeholm, MariaVikberg, Ann-LouiseNorberg, AnnaSandström, HerbertWahlin, AndersGolovleva, Irina
By organisation
OncologyMedical and Clinical GeneticsFamily Medicine
In the same journal
Blood
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 156 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf