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Novel exon 2 α spectrin mutation and intragenic crossover: three morphological phenotypes associated with four distinct α spectrin defects.
Haematologica. 2013 Dec; 98(12):1972-9.H

Abstract

Hereditary pyropoikilocytosis is a severe hemolytic anemia caused by spectrin deficiency and defective spectrin dimer self-association, typically found in African populations. We describe two Utah families of northern European ancestry including 2 propositi with atypical non-microcytic hereditary pyropoikilocytosis, 7 hereditary elliptocytosis members and one asymptomatic carrier. The underlying molecular defect is a novel mutation in the alpha(α) spectrin gene, SPTA(R34P) that impairs spectrin tetramer formation. It is inherited in trans to the hypomorphic SPTA(αLELY) in the 2 propositi and 5 of 7 hereditary elliptocytosis individuals indicating that SPTA(αLELY) is not the sole determinant of the variable clinical expression. α Spectrin mRNA was mildly decreased in all hereditary elliptocytosis subjects, whereas both hereditary pyropoikilocytosis propositi had a severe decrease to ~10% of normal. Genotyping identified a unique SPTA intragenic crossover and uniparental disomy in one hereditary elliptocytosis individual. Two additional crossover events demonstrated the susceptibility of SPTA gene to rearrangement and revealed a novel segregation of the two SPTA(αLELY) mutations. We conclude that the profound phenotypic heterogeneity in these families can be attributed to the SPTA(R34P) mutation in combination with: 1) inheritance in trans of either SPTA(αLELY); or 2) the wild-type SPTA; 3) a decrease of α spectrin mRNA; and 4) SPTA intragenic crossover.

Authors+Show Affiliations

Josef.prchal@hsc.utah.edu.No 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)

Case Reports
Journal Article

Language

eng

PubMed ID

24077844

Citation

Swierczek, Sabina, et al. "Novel Exon 2 Α Spectrin Mutation and Intragenic Crossover: Three Morphological Phenotypes Associated With Four Distinct Α Spectrin Defects." Haematologica, vol. 98, no. 12, 2013, pp. 1972-9.
Swierczek S, Agarwal AM, Naidoo K, et al. Novel exon 2 α spectrin mutation and intragenic crossover: three morphological phenotypes associated with four distinct α spectrin defects. Haematologica. 2013;98(12):1972-9.
Swierczek, S., Agarwal, A. M., Naidoo, K., Lorenzo, F. R., Whisenant, J., Nussenzveig, R. H., Agarwal, N., Coetzer, T. L., & Prchal, J. T. (2013). Novel exon 2 α spectrin mutation and intragenic crossover: three morphological phenotypes associated with four distinct α spectrin defects. Haematologica, 98(12), 1972-9. https://doi.org/10.3324/haematol.2013.086629
Swierczek S, et al. Novel Exon 2 Α Spectrin Mutation and Intragenic Crossover: Three Morphological Phenotypes Associated With Four Distinct Α Spectrin Defects. Haematologica. 2013;98(12):1972-9. PubMed PMID: 24077844.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Novel exon 2 α spectrin mutation and intragenic crossover: three morphological phenotypes associated with four distinct α spectrin defects. AU - Swierczek,Sabina, AU - Agarwal,Archana M, AU - Naidoo,Kubendran, AU - Lorenzo,Felipe R, AU - Whisenant,Jonathan, AU - Nussenzveig,Roberto H, AU - Agarwal,Neeraj, AU - Coetzer,Theresa L, AU - Prchal,Josef T, Y1 - 2013/09/27/ PY - 2013/10/1/entrez PY - 2013/10/1/pubmed PY - 2014/7/16/medline SP - 1972 EP - 9 JF - Haematologica JO - Haematologica VL - 98 IS - 12 N2 - Hereditary pyropoikilocytosis is a severe hemolytic anemia caused by spectrin deficiency and defective spectrin dimer self-association, typically found in African populations. We describe two Utah families of northern European ancestry including 2 propositi with atypical non-microcytic hereditary pyropoikilocytosis, 7 hereditary elliptocytosis members and one asymptomatic carrier. The underlying molecular defect is a novel mutation in the alpha(α) spectrin gene, SPTA(R34P) that impairs spectrin tetramer formation. It is inherited in trans to the hypomorphic SPTA(αLELY) in the 2 propositi and 5 of 7 hereditary elliptocytosis individuals indicating that SPTA(αLELY) is not the sole determinant of the variable clinical expression. α Spectrin mRNA was mildly decreased in all hereditary elliptocytosis subjects, whereas both hereditary pyropoikilocytosis propositi had a severe decrease to ~10% of normal. Genotyping identified a unique SPTA intragenic crossover and uniparental disomy in one hereditary elliptocytosis individual. Two additional crossover events demonstrated the susceptibility of SPTA gene to rearrangement and revealed a novel segregation of the two SPTA(αLELY) mutations. We conclude that the profound phenotypic heterogeneity in these families can be attributed to the SPTA(R34P) mutation in combination with: 1) inheritance in trans of either SPTA(αLELY); or 2) the wild-type SPTA; 3) a decrease of α spectrin mRNA; and 4) SPTA intragenic crossover. SN - 1592-8721 UR - https://www.unboundmedicine.com/medline/citation/24077844/Novel_exon_2_α_spectrin_mutation_and_intragenic_crossover:_three_morphological_phenotypes_associated_with_four_distinct_α_spectrin_defects_ L2 - http://www.haematologica.org/cgi/pmidlookup?view=long&pmid=24077844 DB - PRIME DP - Unbound Medicine ER -