Diagnosing dehydrated hereditary stomatocytosis due to a KCNN4 Gardos channel mutation: understanding challenges through study of a multi‐generational family

• Published in: EJHaem Vol. 2; no. 3; pp. 485 - 487
• Main Authors: Waldstein, Sasha, Arnold‐Croop, Sarah, Carrel, Laura, Eyster, M. Elaine
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.08.2021; John Wiley and Sons Inc; Wiley
• Subjects: Actin; Adducin; Adenosine triphosphatase; Age; Anemia; Ankyrins; Blood; Calcium influx; Cell adhesion; Cell membranes; Channelopathy; Chelation therapy; Chemokine receptors; Cholecystectomy; Collagen (type IV); Dehydration; Erythrocytes; Genes; Glucuronosyltransferase; Glutathione peroxidase; Glycophorin B; Hemoglobin; hereditary anemia; Iron; iron overload; Kell system; Laboratories; Membrane proteins; Mutation; non‐spherocytic hemolytic anemia; Peroxiredoxin; Phospholipids; Potassium; Potassium channels (calcium-gated); Proteins; Short Report; Short Reports; Tropomyosin; iron overload; non‐spherocytic hemolytic anemia; hereditary anemia
• ISSN: 2688-6146; 2688-6146
• DOI: 10.1002/jha2.267

The majority of described DHSt cases result from gain-of-function mutations in the mechanosensitive cation channel gene PIEZO1, leading to an inappropriate increase in calcium influx. Less frequently, gain-of-function mutations have been identified in the Gardos channel gene, KCNN4, that alter calcium sensitivity and result in a more active channel. [...]DHSt due to KCNN4 mutation is aptly termed a Gardos channelopathy [ 2–4]. Though a complex compensatory mechanism has been proposed in those with KCNN4 mutations, the increased cation leak across the red blood cell membrane in cases with either PIEZO1 or KCNN4 mutations is accompanied by intracellular dehydration and the formation of stomatocytes [ 4]. Since the first reports in 2015, to our knowledge, KCNN4 mutations have been identified in ten DHSt families [ 2–6]. Genes screened included: ATP binding cassette subfamily G members (ABCG5 and ABCG8), ATPase phospholipid transporting 11c (ATP11c), collagen type IV alpha 1 chain (COL4A1), erythrocyte membrane protein band 4.1 (EPB41), potassium calcium-activated channel subfamily N member 4 (KCNN4), UDP glucuronosyltransferase family 1 member A6 and A7 (UGT1A6, UGTA17), X-linked Kx blood group (XK), glutathione peroxidase 1 (GPX1), glycophorin A (GYPA), glycophorin B (GYPB), CD47, adducin 1 (ADD1), adducin 2 (ADD2), atypical chemokine receptor 1 (ACKR1), ankyrin 1 (ANK1), dematin actin-binding protein (DMTN), kell system (KEL), intercellular adhesion molecule 4 (ICAM4), peroxiredoxin 2 (PRDX2), erythrocyte tropomodulin (TMOD1), tropomyosin 1 (TPM1), TRIO, and F-Actin binding protein (TRIOBP).