A 7-year-old boy presents with intermittent jaundice, fatigue, and splenomegaly. His mother underwent cholecystectomy for pigment gallstones at age 22. Laboratory findings show hemoglobin 9.0 g/dL, MCHC 37 g/dL, reticulocytosis 8%, and spherocytes on peripheral smear with a negative direct antiglobulin test. Eosin-5-maleimide (EMA) binding by flow cytometry is decreased. Genetic testing reveals a heterozygous mutation on the structure marked **A** in the diagram. Which of the following best explains the molecular basis of this patient's hereditary spherocytosis?

Question

Accepted Answer

C. Defect in β-spectrin (SPTB) causing disruption of vertical membrane–cytoskeleton interactions and loss of biconcave disc shape. ## Why β-spectrin (SPTB) defect is correct

The patient has a heterozygous mutation on chromosome 14q23, which encodes SPTB (β-spectrin). This is the most common autosomal dominant form of hereditary spherocytosis after ankyrin mutations. β-spectrin is a critical component of the red-cell membrane cytoskeleton that maintains the vertical linkage between the plasma membrane and the underlying spectrin lattice. Mutations in SPTB disrupt this vertical defect, leading to loss of membrane microvesicles, reduced surface area-to-volume ratio, and conversion of biconcave discs into rigid spherocytes. These spherocytes are sequestered and destroyed in the splenic cords of Billroth, producing extravascular hemolysis. The decreased EMA binding on flow cytometry is the current gold standard for diagnosing membrane protein defects in hereditary spherocytosis and is consistent with spectrin deficiency. The autosomal dominant inheritance pattern (mother with pigment gallstones) and the clinical presentation of moderate hemolytic anemia with splenomegaly are typical of SPTB mutations.

## Why each distractor is wrong

- **Ankyrin (ANK1) defect**: While ANK1 mutations are the most common cause of autosomal dominant HS overall, the question explicitly states the mutation is on chromosome 14q23, which is the location of SPTB, not ANK1 (which is on chromosome 8p11). ANK1 defects prevent linkage between spectrin and band 3, but this is not the genetic location identified in this patient.

- **α-spectrin (SPTA1) defect**: SPTA1 mutations cause autosomal recessive hereditary spherocytosis and are typically more severe than this patient's presentation. The patient is heterozygous with a chromosome 14 mutation, not an SPTA1 mutation. SPTA1 is located on chromosome 1, not chromosome 14.

- **Band 3 (SLC4A1) defect**: Band 3 mutations cause autosomal dominant HS but are located on chromosome 17q21, not chromosome 14q23. While band 3 is important for chloride-bicarbonate exchange and membrane stability, the genetic location in this case points to SPTB.

**High-Yield:** SPTB (β-spectrin) mutations on chromosome 14q23 are the second most common cause of autosomal dominant hereditary spherocytosis; they disrupt vertical membrane–cytoskeleton interactions, causing spherocyte formation and extravascular hemolysis in the spleen.

[cite: Harrison 21e Ch 95; Bolton-Maggs HS Br J Haematol 2012]

Answer

A. Defect in ankyrin (ANK1) preventing linkage between spectrin and band 3 protein

Answer

B. Defect in α-spectrin (SPTA1) causing severe autosomal recessive hemolytic anemia

Answer

D. Defect in band 3 (SLC4A1) impairing chloride-bicarbonate exchange in red cells

Explanation

Why β-spectrin (SPTB) defect is correct

Why each distractor is wrong

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