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Structural and functional heterogeneity of alpha spectrin mutations involving the spectrin heterodimer self-association site: relationships to hematologic expression of homozygous hereditary elliptocytosis and hereditary pyropoikilocytosis.
Blood. 1990 Jun 01; 75(11):2235-44.Blood

Abstract

Defects involving alpha spectrin (Sp) are found in patients with hereditary elliptocytosis and a related disorder, hereditary pyropoikilocytosis (HPP). We have previously found that the severity of hemolysis was related to the total spectrin content of the cells and the percentage of unassembled dimeric Sp (SpD) in the membranes, which, in turn, reflected the amount of mutant Sp in the cell. However, no data are available comparing differences in the function of various alpha Sp mutations to clinical severity. We now report studies of nine homozygotes or double heterozygotes for four alpha Sp mutations: alpha 1/74, alpha 1/46, alpha 1/65, and alpha 1/61, whose red blood cells (RBCs) contained only the mutant Sp and no normal Sp. Sp alpha 1/74, Sp alpha 1/46, and alpha 1/65 homozygotes differed strikingly in the severity of hemolysis that correlated with the severity of mutant Sp dysfunction, as reflected by the fraction of unassembled SpD in the membranes and the self-association of mutant Sp on inside-out vesicles. Homozygotes for Sp alpha 1/74 had a very severe hemolytic anemia and their SpD were virtually incapable of self-association, whereas SpD alpha 1/46 were not as severely affected. The Sp alpha 1/65 homozygotes had a relatively mild hemolytic anemia and their SpD showed the least impairment of function. Ultrastructural examination of membrane skeletons from subjects whose SpD self-association was severely impaired showed gross skeletal disruption and loss of hexagonal structure. In striking contrast, the homozygote for the mildly dysfunctional Sp alpha 1/65 had only a moderate disruption of the skeleton. Some of the homozygous or doubly heterozygous subjects also exhibited a partial deficiency of Sp that correlated with a RBC morphology characteristic of HPP, namely, marked microspherocytosis with virtual absence of elliptocytes. These data demonstrate striking differences in the function and structure of various alpha Sp mutants that underlie differences in clinical expression.

Authors+Show Affiliations

Department of Biomedical Research, St Elizabeth's Hospital, Tufts University School of Medicine, Boston, MA 02135.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

2346784

Citation

Coetzer, T, et al. "Structural and Functional Heterogeneity of Alpha Spectrin Mutations Involving the Spectrin Heterodimer Self-association Site: Relationships to Hematologic Expression of Homozygous Hereditary Elliptocytosis and Hereditary Pyropoikilocytosis." Blood, vol. 75, no. 11, 1990, pp. 2235-44.
Coetzer T, Palek J, Lawler J, et al. Structural and functional heterogeneity of alpha spectrin mutations involving the spectrin heterodimer self-association site: relationships to hematologic expression of homozygous hereditary elliptocytosis and hereditary pyropoikilocytosis. Blood. 1990;75(11):2235-44.
Coetzer, T., Palek, J., Lawler, J., Liu, S. C., Jarolim, P., Lahav, M., Prchal, J. T., Wang, W., Alter, B. P., & Schewitz, G. (1990). Structural and functional heterogeneity of alpha spectrin mutations involving the spectrin heterodimer self-association site: relationships to hematologic expression of homozygous hereditary elliptocytosis and hereditary pyropoikilocytosis. Blood, 75(11), 2235-44.
Coetzer T, et al. Structural and Functional Heterogeneity of Alpha Spectrin Mutations Involving the Spectrin Heterodimer Self-association Site: Relationships to Hematologic Expression of Homozygous Hereditary Elliptocytosis and Hereditary Pyropoikilocytosis. Blood. 1990 Jun 1;75(11):2235-44. PubMed PMID: 2346784.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Structural and functional heterogeneity of alpha spectrin mutations involving the spectrin heterodimer self-association site: relationships to hematologic expression of homozygous hereditary elliptocytosis and hereditary pyropoikilocytosis. A1 - Coetzer,T, AU - Palek,J, AU - Lawler,J, AU - Liu,S C, AU - Jarolim,P, AU - Lahav,M, AU - Prchal,J T, AU - Wang,W, AU - Alter,B P, AU - Schewitz,G, PY - 1990/6/1/pubmed PY - 1990/6/1/medline PY - 1990/6/1/entrez SP - 2235 EP - 44 JF - Blood JO - Blood VL - 75 IS - 11 N2 - Defects involving alpha spectrin (Sp) are found in patients with hereditary elliptocytosis and a related disorder, hereditary pyropoikilocytosis (HPP). We have previously found that the severity of hemolysis was related to the total spectrin content of the cells and the percentage of unassembled dimeric Sp (SpD) in the membranes, which, in turn, reflected the amount of mutant Sp in the cell. However, no data are available comparing differences in the function of various alpha Sp mutations to clinical severity. We now report studies of nine homozygotes or double heterozygotes for four alpha Sp mutations: alpha 1/74, alpha 1/46, alpha 1/65, and alpha 1/61, whose red blood cells (RBCs) contained only the mutant Sp and no normal Sp. Sp alpha 1/74, Sp alpha 1/46, and alpha 1/65 homozygotes differed strikingly in the severity of hemolysis that correlated with the severity of mutant Sp dysfunction, as reflected by the fraction of unassembled SpD in the membranes and the self-association of mutant Sp on inside-out vesicles. Homozygotes for Sp alpha 1/74 had a very severe hemolytic anemia and their SpD were virtually incapable of self-association, whereas SpD alpha 1/46 were not as severely affected. The Sp alpha 1/65 homozygotes had a relatively mild hemolytic anemia and their SpD showed the least impairment of function. Ultrastructural examination of membrane skeletons from subjects whose SpD self-association was severely impaired showed gross skeletal disruption and loss of hexagonal structure. In striking contrast, the homozygote for the mildly dysfunctional Sp alpha 1/65 had only a moderate disruption of the skeleton. Some of the homozygous or doubly heterozygous subjects also exhibited a partial deficiency of Sp that correlated with a RBC morphology characteristic of HPP, namely, marked microspherocytosis with virtual absence of elliptocytes. These data demonstrate striking differences in the function and structure of various alpha Sp mutants that underlie differences in clinical expression. SN - 0006-4971 UR - https://www.unboundmedicine.com/medline/citation/2346784/Structural_and_functional_heterogeneity_of_alpha_spectrin_mutations_involving_the_spectrin_heterodimer_self_association_site:_relationships_to_hematologic_expression_of_homozygous_hereditary_elliptocytosis_and_hereditary_pyropoikilocytosis_ L2 - http://www.diseaseinfosearch.org/result/3352 DB - PRIME DP - Unbound Medicine ER -