title: Congenital dyserythropoietic anemia type III (CDA III) is caused by a mutation in kinesin family member, KIF23.
abstract: 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.
authors.affiliation: Department of Radiation Sciences, Umeå University, Umeå, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Liljeholm
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Irvine
authors.forename: Ann-Louise
authors.initials: AL
authors.lastname: Vikberg
authors.forename: Anna
authors.initials: A
authors.lastname: Norberg
authors.forename: Stacy
authors.initials: S
authors.lastname: Month
authors.forename: Herbert
authors.initials: H
authors.lastname: Sandström
authors.forename: Anders
authors.initials: A
authors.lastname: Wahlin
authors.forename: Masanori
authors.initials: M
authors.lastname: Mishima
authors.forename: Irina
authors.initials: I
authors.lastname: Golovleva
mesh_terms: D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000742:Anemia, Dyserythropoietic, Congenital / Q000209:etiology* / Q000473:pathology; D014408:Biomarkers, Tumor / Q000235:genetics*; D020090:Chromosome Segregation; D048749:Cytokinesis; D005260:Female; D006367:HeLa Cells; D006801:Humans; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D016133:Polymerase Chain Reaction; D011379:Prognosis; D017386:Sequence Homology, Amino Acid
chemical_list: D014408:Biomarkers, Tumor; C092935:KIF23 protein, human; D008869:Microtubule-Associated Proteins