KCNN4 – Dehydrated Hereditary Stomatocytosis

KCNN4 encodes the Ca²⁺-activated K⁺ channel KCa3.1 (the Gardos channel) involved in erythrocyte volume regulation. Pathogenic KCNN4 variants cause dehydrated hereditary stomatocytosis (DHS; MONDO:0017910), a rare autosomal dominant hemolytic anemia characterized by increased red cell cation permeability and iron overload.

Genetic screening of DHS cohorts identified KCNN4 variants in 13 unrelated families, totaling 13 probands with autosomal dominant inheritance (13 probands; PMID:36031591). Segregation of KCNN4 variants with disease was confirmed in two kindreds (PMID:26198474, PMID:26148990). Reported variant spectrum includes missense substitutions such as c.1018C>A (p.His340Asn) (PMID:36003639).

Additional case reports describe de novo p.Val222Leu and p.His340Asn in individuals presenting with severe or transient anemia but lacking overt erythrocyte dehydration (PMID:36003639). A large retrospective series of 126 hereditary xerocytosis patients further distinguished KCNN4-related “Gardos channelopathy” by more severe anemia, chronic hemolysis, hyperferritinemia, and inefficient response to splenectomy—without clear indicators of red cell dehydration (PMID:30655378).

Functional studies demonstrate that mutations such as p.Arg352His hyperactivate the Gardos channel, increasing Ca²⁺ sensitivity and K⁺ efflux in circulating erythrocytes and ex vivo–differentiated CD34⁺ erythroblasts. Electrophysiological recordings in Xenopus oocytes and patch-clamp assays in HEK293 cells confirm gain-of-function mechanisms consistent with DHS pathophysiology (PMID:28496185, PMID:26148990).

Phenotypic heterogeneity is evident: some gain-of-function variants (e.g., p.His340Asn, p.Val222Leu) confer channel hypersensitivity without overt stomatocytosis, suggesting additional modifiers influence red cell hydration status and clinical severity (PMID:36003639).

Integration of genetic and experimental evidence supports a Strong clinical validity classification for KCNN4 in DHS. Autosomal dominant gain-of-function variants in KCNN4 reliably predict disease, and functional assays offer mechanistic confirmation. Key Take-home: KCNN4 gain-of-function mutations underlie an autosomal dominant Gardos channelopathy, warranting inclusion of KCNN4 in diagnostic panels for hemolytic anemia and guiding management of iron overload and splenectomy outcomes.

References

• Scientific reports • 2017 • 'Gardos Channelopathy': a variant of hereditary Stomatocytosis with complex molecular regulation. PMID:28496185
• Blood • 2015 • A mutation in the Gardos channel is associated with hereditary xerocytosis. PMID:26148990
• Blood • 2015 • Mutations in the Gardos channel (KCNN4) are associated with hereditary xerocytosis. PMID:26198474
• Clinical genetics • 2022 • A Gardos channelopathy associated with nonimmune hydrops and fetal loss. PMID:36031591
• Frontiers in physiology • 2022 • New KCNN4 Variants Associated With Anemia: Stomatocytosis Without Erythrocyte Dehydration. PMID:36003639
• Haematologica • 2019 • Clinical and biological features in PIEZO1-hereditary xerocytosis and Gardos channelopathy: a retrospective series of 126 patients. PMID:30655378

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