Spherocytosis, Type 2

A number sign (#) is used with this entry because spherocytosis type 2 (SPH2) is caused by heterozygous mutation in the SPTB gene (182870) on chromosome 14q23. Some patients have been reported with homozygous or compound heterozygous mutations.

Description

Hereditary spherocytosis refers to a group of heterogeneous disorders that are characterized by the presence of spherical-shaped erythrocytes (spherocytes) on the peripheral blood smear. The disorders are characterized clinically by anemia, jaundice, and splenomegaly, with variable severity. Common complications include cholelithiasis, hemolytic episodes, and aplastic crises (review by Perrotta et al., 2008).

For a general description and a discussion of genetic heterogeneity of hereditary spherocytosis, see 182900.

Clinical Features

In 2 of 4 families with autosomal dominant hereditary spherocytosis, Goodman et al. (1982) identified an approximately 37% reduction in binding of spectrin to protein 4.1 (EPB41; 130500) due to a defective spectrin molecule. All other type I membrane skeletal interactions were found to be normal.

In 1 of 6 families with autosomal dominant hereditary spherocytosis, Wolfe et al. (1982) identified an apparently identical defect in which approximately 40% of beta-spectrin was unable to bind protein 4.1. As a consequence, the protein 4.1-stimulated binding of spectrin to F-actin was greatly reduced. All other spectrin functions remained intact. This form of HS was designated HS(Sp-4.1) (Becker et al., 1987).

Basseres et al. (2001) reported a 25-year-old woman of Italian origin who presented with hemolytic anemia with splenomegaly, hyperbilirubinemia, increased osmotic fragility of the red cells, and many spherocytes and acanthocytes in the blood smear.

Maciag et al. (2009) found that levels of SPTB mRNA were 20 to 80% lower in unrelated patients with hereditary spherocytosis compared to controls.

Molecular Genetics

Becker et al. (1993) noted that there is asymmetry in the relative synthetic rates of alpha- and beta-spectrin; the synthesis of alpha- and beta-spectrin is 3-fold in excess of beta-spectrin synthesis. Spectrin assembly on the membrane appears to be rate limited by the beta chain. Therefore, one could predict that defects in beta-spectrin would be manifest in the heterozygous state and result in dominantly inherited conditions. In contrast, defects in alpha-spectrin may not be manifest until the homozygous state is reached, since the alpha chains are synthesized in excess of the beta chains. Becker et al. (1993) were the first to identify a beta-spectrin mutation (W202R; 182870.0007) as the cause of autosomal dominant hereditary spherocytosis. The family had previously been reported by Wolfe et al. (1982).

In a 25-year-old woman with spherocytosis type 2, Basseres et al. (2001) identified a heterozygous deletion in the SPTB gene (182870.0014). The mutation was not present in her unaffected parents but was present in her affected brother, suggesting mosaicism.

By direct sequencing of the SPTB gene in patients with spherocytosis and decreased levels of beta-spectrin, maciag et al. (2009) identified 5 different pathogenic mutations in the SPTB gene (see, e.g., 182870.0015). Affected members of 1 family showed 2 mutations, consistent with the greatest decrease (80%) in SPTB mRNA.