SPTB – Hereditary Elliptocytosis

β-Spectrin, encoded by SPTB, is a key component of the erythrocyte membrane skeleton that stabilizes red blood cell shape by forming spectrin tetramers. Heterozygous or homozygous mutations in SPTB disrupt spectrin self-association and lead to autosomal dominant hereditary elliptocytosis (HE), characterized by elliptically shaped erythrocytes and hemolytic anemia.

The first SPTB point mutation associated with HE was identified in a consanguineous family: a homozygous alanine-to-proline substitution in the β-spectrin C-terminus caused severe neonatal hemolysis with poikilocytosis, and heterozygous parents and offspring exhibited milder elliptocytosis, demonstrating segregation in at least 5 family members ([PMID:1975598]). Subsequent reports have confirmed autosomal dominant inheritance in additional pedigrees.

At least 4 distinct SPTB variants spanning missense, splice-site and insertional frameshift mutations have been described in HE probands: c.2303G>A (p.Gly768Asp) ([PMID:38148910]), c.6219_6219+13del (splice donor; exon skipping) ([PMID:9207403]), and c.2048_2049dup (p.Asp684ArgfsTer?) and c.6135_6136dup (p.Lys2046ArgfsTer?) ([PMID:2070088]). These variants illustrate the diverse mutational mechanisms impairing β-spectrin function.

Biochemical and cell-based assays demonstrate a dominant-negative mechanism: mutant β-spectrin variants reduce the spectrin dimer self-association constant, elevate the percentage of unassembled dimers, and produce aberrant α-spectrin proteolytic fragments, correlating with decreased membrane stability and elliptical erythrocyte shape ([PMID:8136282]; [PMID:1975598]).

Conversely, large in‐frame insertions such as spectrin Detroit (84 kDa insertion) allow near-normal dimerization with α-spectrin and minimal elliptocytosis, highlighting variant-specific effects on clinical expressivity ([PMID:1536811]).

Overall, extensive genetic and functional evidence supports a definitive association between SPTB mutations and autosomal dominant HE. Molecular testing of SPTB informs accurate diagnosis, guides family counseling, and may enable future therapies targeting spectrin tetramer assembly. Key take-home: SPTB variant screening is essential for precise diagnosis and management of hereditary elliptocytosis.

References

• The Journal of clinical investigation • 1990 • Point mutation in the beta-spectrin gene associated with alpha I/74 hereditary elliptocytosis. Implications for the mechanism of spectrin dimer self-association. PMID:1975598
• British journal of haematology • 1992 • A large erythroid spectrin beta-chain variant. PMID:1536811
• British journal of haematology • 1997 • Beta-spectrin Campinas: a novel shortened beta-chain variant associated with skipping of exon 30 and hereditary elliptocytosis. PMID:9207403
• Blood • 1991 • An insertional frameshift mutation of the beta-spectrin gene associated with elliptocytosis in spectrin nice (beta 220/216). PMID:2070088
• British journal of haematology • 1993 • Molecular basis of clinical and morphological heterogeneity in hereditary elliptocytosis (HE) with spectrin alpha I variants. PMID:8136282
• Frontiers in medicine • 2023 • Case report: Whole-exome sequencing for a hereditary elliptocytosis case with an unexpectedly low HbA1c. PMID:38148910

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