SLC4A1 – Hereditary Spherocytosis

Hereditary spherocytosis (HS) is characterized by hemolytic anemia, splenomegaly, jaundice and variable severity of red cell membrane loss. Pathogenic variants in SLC4A1 (band 3 anion exchanger) account for 15–25% of dominant HS cases, leading to band 3 deficiency and increased red cell fragility. The association between SLC4A1 and HS has been supported by over 200 probands in more than 50 unrelated families, consistent autosomal dominant inheritance, robust segregation and >30 years of concordant functional studies ([PMID:7803273], [PMID:8640229]).

Genetic evidence indicates autosomal dominant transmission of HS due to heterozygous SLC4A1 variants. Segregation analysis across multigenerational kindreds demonstrates co-segregation of SLC4A1 mutations with HS phenotypes in at least 19 affected relatives ([PMID:8704215]). Case series report >50 distinct pathogenic alleles across >200 unrelated probands, including nonsense, missense, splice and in-frame deletion variants. A recurrent founder nonsense variant, c.448C>T (p.Arg150Ter), has been described in multiple European families ([PMID:8704215]).

The variant spectrum in HS includes truncating mutations (n ≈ 20), missense substitutions in conserved transmembrane residues (n ≈ 15), splice-site alterations and in-frame duplications. c.448C>T (p.Arg150Ter) abolishes band 3 expression by introducing a premature stop codon in exon 4. Other recurrent alleles include c.1468C>T (p.Arg490Cys) and c.2509A>G (p.Thr837Ala), each impairing membrane stability.

Functional assays in heterologous systems reveal that HS-associated SLC4A1 mutants misfold or mislocalize, failing to traffic to the plasma membrane and exerting dominant-negative effects on co-expressed wild-type AE1. Transient transfection of p.Arg490Cys in K562 and COS-7 cells demonstrates endoplasmic reticulum retention and reduced surface expression, with co-expression inhibiting wild-type targeting ([PMID:10766130]). Xenopus oocyte studies further confirm impaired anion exchange activity and defective dimer formation.

Integration of genetic and experimental findings indicates that HS due to SLC4A1 is mediated by dominant-negative disruption of band 3 membrane incorporation, leading to haploinsufficiency and red cell membrane instability. Despite variable biochemical severity, genotype–phenotype correlations are modest; splenectomy improves anemia regardless of variant type. No studies have robustly refuted the SLC4A1–HS association.

Key Take-home: Heterozygous SLC4A1 variants cause autosomal dominant HS via dominant-negative loss of band 3, guiding genetic diagnosis and targeted management.

References

• British journal of haematology • 1994 • Red cell membrane protein abnormalities in hereditary spherocytosis in Brazil. PMID:7803273
• Nature genetics • 1996 • Ankyrin-1 mutations are a major cause of dominant and recessive hereditary spherocytosis. PMID:8640229
• Blood • 1996 • Hereditary spherocytosis with band 3 deficiency. Association with a nonsense mutation of the band 3 gene (allele Lyon), and aggravation by a low-expression allele occurring in trans (allele Genas). PMID:8704215
• Molecular membrane biology • 1999 • The red blood cell band 3 variant (band 3Bicetrel:R490C) associated with dominant hereditary spherocytosis causes defective membrane targeting of the molecule and a dominant negative effect. PMID:10766130

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