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

作者：Swierczek Sabina; Agarwal Archana M; Naidoo Kubendran; Lorenzo Felipe R; Whisenant Jonathan; Nussenzveig Roberto H; Agarwal Neeraj; Coetzer Theresa L; Prchall Josef T^*

来源：Haematologica-The Hematology Journal, 2013, 98(12): 1972-1979.

DOI：10.3324/haematol.2013.086629

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(alpha) spectrin gene, SPTA(R84P) that impairs spectrin tetramer formation. It is inherited in trans to the hypomorphic SPTA(alpha LELY) in the 2 propositi and 5 of 7 hereditary elliptocytosis individuals indicating that SPTA(alpha LELY) is not the sole determinant of the variable clinical expression. alpha Spectrin mRNA was mildly decreased in all hereditary elliptocytosis subjects, whereas both hereditary pyropoikilocytosis propositi had a severe decrease to similar 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(alpha LELY) mutations. We conclude that the profound phenotypic heterogeneity in these families can be attributed to the SPTA(R84P) mutation in combination with: 1) inheritance in trans of either SPTA(alpha LELY); or 2) the wild-type SPTA; 3) a decrease of alpha spectrin mRNA; and 4) SPTA intragenic crossover.

• 出版日期2013-12