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

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(?) spectrin gene, SPTA(R34P) that impairs spectrin tetramer formation. It is inherited in trans to the hypomorphic SPTA(?LELY) in the 2 propositi and 5 of 7 hereditary elliptocytosis individuals indicating that SPTA(?LELY) is not the sole determinant of the variable clinical expression. ? 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(?LELY) 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(?LELY); or 2) the wild-type SPTA; 3) a decrease of ? spectrin mRNA; and 4) SPTA intragenic crossover.

SUBMITTER: Swierczek S

PROVIDER: S-EPMC3856973 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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

Swierczek Sabina S Agarwal Archana M AM Naidoo Kubendran K Lorenzo Felipe R FR Whisenant Jonathan J Nussenzveig Roberto H RH Agarwal Neeraj N Coetzer Theresa L TL Prchal Josef T JT

Haematologica 20130927 12

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 ...[more]

PMID: 24077844

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Dataset Information

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

Publications

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

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