Novel exon 2 α spectrin mutation and intragenic crossover: three morphological phenotypes associated with four distinct α spectrin defects

Autor: Sabina Swierczek, Archana M. Agarwal, Kubendran Naidoo, Felipe R. Lorenzo, Jonathan Whisenant, Roberto H. Nussenzveig, Neeraj Agarwal, Theresa L. Coetzer, Josef T. Prchal
Jazyk: angličtina
Rok vydání: 2013
Předmět:
Zdroj: Haematologica, Vol 98, Iss 12 (2013)
Druh dokumentu: article
ISSN: 0390-6078
1592-8721
DOI: 10.3324/haematol.2013.086629
Popis: 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, SPTAR34P that impairs spectrin tetramer formation. It is inherited in trans to the hypomorphic SPTAαLELY in the 2 propositi and 5 of 7 hereditary elliptocytosis individuals indicating that SPTAαLELY 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 SPTAαLELY mutations. We conclude that the profound phenotypic heterogeneity in these families can be attributed to the SPTAR34P mutation in combination with: 1) inheritance in trans of either SPTAαLELY; or 2) the wild-type SPTA; 3) a decrease of α spectrin mRNA; and 4) SPTA intragenic crossover.
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