ABCB6 – Familial Pseudohyperkalemia

Familial pseudohyperkalemia (FP) is an autosomal dominant red blood cell trait characterized by temperature-dependent leakage of potassium from erythrocytes, resulting in spuriously elevated serum potassium levels without clinical signs of hyperkalemia. ABCB6 encodes an ATP-binding cassette transporter on the erythrocyte membrane bearing the Langereis blood group antigen. Differentiating FP from true hyperkalemia is critical to avoid inappropriate potassium-lowering interventions.

In a pedigree study of three multigenerational families, two novel heterozygous missense variants at codon 375 of ABCB6 (c.1123C>T (p.Arg375Trp) and c.1124G>A (p.Arg375Gln)) cosegregated with FP in 20 affected individuals (PMID:23180570). A separate case report described a 56-year-old female with asymptomatic hyperkalemia whose blood exhibited cold-induced K^+ leaks; sequencing confirmed a heterozygous c.1123C>T (p.Arg375Trp) variant, establishing FP (PMID:35372423).

FP follows an autosomal dominant inheritance pattern with at least 21 unrelated probands and multiple intergenerational transmissions. The variant spectrum is dominated by missense changes impacting transporter permeability, most recurrently c.1123C>T (p.Arg375Trp).

Functional assays in HEK-293 cells expressing ABCB6 mutants (including R276W, R723Q, and V454A) demonstrated significantly elevated K^+ and Rb^+ efflux compared to wild-type, with heterozygous R276W and compound R276W/R723Q genotypes showing pronounced passive leak (PMID:27151991). Ex vivo storage studies of mutant RBCs recapitulated cold-induced K^+ release observed clinically.

These findings support a temperature-sensitive gain-of-function mechanism whereby mutant ABCB6 channels increase passive ion conductance at reduced temperatures, leading to pseudohyperkalemia. No studies to date dispute this association.

Overall, the ABCB6–FP relationship is classified as Strong given robust segregation across multiple families and concordant functional data. Genetic testing for ABCB6 missense variants enables definitive diagnosis, guiding clinical management by preventing unwarranted potassium-lowering therapies.

Key Take-home: Heterozygous ABCB6 missense mutations cause autosomal dominant familial pseudohyperkalemia via temperature-dependent RBC K^+ leak, warranting targeted genetic testing in suspected cases.

References

• American Journal of Hematology • 2013 • Missense mutations in the ABCB6 transporter cause dominant familial pseudohyperkalemia. PMID:23180570
• Frontiers in Medicine • 2022 • Case Report: Familial Pseudohyperkalemia Due to Red Blood Cell Membrane Leak in a Chinese Patient. PMID:35372423
• Haematologica • 2016 • Functional characterization of novel ABCB6 mutations and their clinical implications in familial pseudohyperkalemia. PMID:27151991

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