title: Normoblastosis, a murine model for ankyrin-deficient hemolytic anemia, is caused by a hypomorphic mutation in the erythroid ankyrin gene Ank1.
abstract: Ankyrin deficiency is one of the most common causes of hereditary spherocytosis in humans. A spontaneous mutation, normoblastosis (Ank1nb), discovered in 1969 in a mouse stock maintained at the Jackson Laboratory, provides an important animal model for these human ankyrin-deficient anemias. Study of this model has led to the finding of multiple isoforms of Ank1 as well as Ank1nb-related pathology in nonerythroid tissues. To enhance the usefulness of this model, we have identified the Ank1nb mutation as the deletion of a guanosine residue in exon 36 of the erythroid ankyrin gene (Ank1). This results in a frame shift that introduces a stop 13 codons downstream and predicts a 157 kDa nb-ankyrin lacking the regulatory domain but including intact membrane- and spectrin-binding domains. By epitope scanning on immunoblots, we show that a previously reported protein (p150) found in nb reticulocytes is the predicted nb-ankyrin. Existing evidence indicates that this protein is functional, making the normoblastosis mutation a hypomorph rather than a null as originally thought. The nb-ankyrin provides an explanation for the milder phenotype displayed by nb/nb animals relative to the murine spectrin-deficient anemias, spherocytosis (Spna1(sph), Spna1(sph-1J), Spna1(sph-2BC), Spna1(sph-DEM)) and jaundiced (Spnb1(ja)), and suggests that truncated ankyrins could be useful in gene replacement therapy.
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609, USA. cb@jax.org
authors.forename: Connie S
authors.initials: CS
authors.lastname: Birkenmeier
authors.forename: Elaine J
authors.initials: EJ
authors.lastname: Gifford
authors.forename: Jane E
authors.initials: JE
authors.lastname: Barker
mesh_terms: D017398:Alternative Splicing; D000743:Anemia, Hemolytic / Q000235:genetics*; D000818:Animals; D017487:Ankyrins / Q000172:deficiency / Q000235:genetics*; D001483:Base Sequence; D017931:DNA Primers; D004195:Disease Models, Animal; D005091:Exons / Q000235:genetics; D007438:Introns / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics; D017384:Sequence Deletion
chemical_list: C491707:Ank1 protein, mouse; D017487:Ankyrins; D017931:DNA Primers; D012333:RNA, Messenger