Novel Exon 2 α Spectrin Mutation and Intragenic Crossover: Three Morphological Phenotypes Associated with Four Distinct α Spectrin Defects

Overview

Journal Haematologica

Specialty Hematology

Date 2013 Oct 1

PMID 24077844

Citations 1

Authors

Sabina Swierczek

Archana M Agarwal

Kubendran Naidoo

Felipe R Lorenzo

Jonathan Whisenant

Roberto H Nussenzveig

Neeraj Agarwal

Theresa L Coetzer

Josef T Prchal

Affiliations

Soon will be listed here.

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.

Citing Articles

Severe nondominant hereditary spherocytosis due to uniparental isodisomy at the SPTA1 locus.

Bogardus H, Schulz V, Maksimova Y, Miller B, Li P, Forget B Haematologica. 2014; 99(9):e168-70.

PMID: 24895341 PMC: 4562552. DOI: 10.3324/haematol.2014.110312.

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