Causes of Hereditary Spherocytosis
Hereditary spherocytosis is caused by genetic mutations in red blood cell membrane proteins that connect the lipid bilayer to the underlying cytoskeleton, resulting in loss of membrane stability and surface area. 1, 2
Genetic Basis
The molecular defects in hereditary spherocytosis stem from mutations in five key genes encoding red cell membrane and skeletal proteins 1:
- Ankyrin-1 (ANK1) - Most common cause, accounting for approximately 56% of cases 3
- Beta-spectrin (SPTB) - Second most common, accounting for approximately 43% of cases 3
- Alpha-spectrin (SPTA1) - Less common cause 1
- Band 3/Anion exchanger 1 (SLC4A1) - Less common cause 1
- Protein 4.2 (EPB42) - Least common cause 1
Inheritance Patterns
Hereditary spherocytosis demonstrates autosomal dominant inheritance in approximately 75% of cases. 1 The remaining cases show recessive or nondominant patterns, most commonly associated with ANK1, SPTA1, and SPTB gene mutations 1. De novo mutations occur in a substantial proportion of families, with studies showing approximately 46% (6 of 13 families) having spontaneous new mutations 3.
Molecular Mechanisms
The pathophysiology involves two distinct mechanisms depending on which protein is affected 2:
- Vertical defects - Mutations affecting proteins that link the lipid bilayer to the membrane skeleton (ankyrin, band 3, protein 4.2) result in loss of membrane cohesion, leading to surface area loss and spherocyte formation 2
- Horizontal defects - Mutations affecting spectrin proteins involved in lateral interactions of the membrane skeleton lead to decreased mechanical stability and membrane fragmentation 2
Types of Mutations
In dominant hereditary spherocytosis, nonsense and frameshift mutations predominate in ankyrin, band 3, and beta-spectrin genes. 4 Nearly every family has a unique mutation, with no single frequent defect identified 4.
For recessive cases, compound heterozygosity is the typical pattern 4:
- Ankyrin defects: promoter or 5'-untranslated region mutation paired with a missense mutation 4
- Alpha-spectrin defects: low expression allele combined with a missense mutation 4
- Protein 4.2 defects: various mutation combinations 4
Pathophysiologic Consequences
The membrane protein defects lead to progressive membrane instability 5, 2:
- Loss of membrane surface area without proportional loss of cell volume creates the characteristic spherical shape 2
- Reduced membrane elasticity and mechanical stability 1
- Vesiculation and shedding of small membrane fragments 4
- Decreased red cell deformability leading to splenic sequestration and premature hemolysis 5
The severity of disease correlates directly with the extent of membrane surface area loss. 2 Patients with moderate to severe spherocytosis have short-lived erythrocytes with prominent decreases in membrane stability and deformability, while mild cases show less pronounced deformability reduction allowing prolonged red cell lifespan 5.