Novel exon 2 α spectrin mutation and intragenic crossover: three morphological phenotypes associated with four distinct α spectrin defects
Sabina Swierczek,
Archana M. Agarwal,
Kubendran Naidoo,
Felipe R. Lorenzo,
Jonathan Whisenant,
Roberto H. Nussenzveig,
Neeraj Agarwal,
Theresa L. Coetzer,
Josef T. Prchal
Affiliations
Sabina Swierczek
Hematology, University of Utah and VAH, Salt Lake City, UT, USA
Archana M. Agarwal
Department of Pathology, University of Utah, Salt Lake City, UT, USA;Special Genetics, ARUP Laboratories, Salt Lake City, UT, USA
Kubendran Naidoo
Department of Molecular Medicine and Haematology, National Health Laboratory Service, University of the Witwatersrand, Faculty of Health Sciences, School of Pathology, Johannesburg, South Africa
Felipe R. Lorenzo
Hematology, University of Utah and VAH, Salt Lake City, UT, USA
Jonathan Whisenant
Utah Cancer Specialists, Salt Lake City, USA
Roberto H. Nussenzveig
Special Genetics, ARUP Laboratories, Salt Lake City, UT, USA
Neeraj Agarwal
Hematology, University of Utah and VAH, Salt Lake City, UT, USA
Theresa L. Coetzer
Department of Molecular Medicine and Haematology, National Health Laboratory Service, University of the Witwatersrand, Faculty of Health Sciences, School of Pathology, Johannesburg, South Africa
Josef T. Prchal
Hematology, University of Utah and VAH, Salt Lake City, UT, USA;Department of Pathology, University of Utah, Salt Lake City, UT, USA;Special Genetics, ARUP Laboratories, Salt Lake City, UT, USA
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.
