PIEZO1 – Dehydrated hereditary stomatocytosis

Dehydrated hereditary stomatocytosis (DHS) is a rare, autosomal dominant hemolytic anemia characterized by erythrocyte dehydration due to increased cation leak and elevated mean corpuscular hemoglobin concentration. PIEZO1 encodes a mechanosensitive ion channel critical for red blood cell volume homeostasis and was first implicated in DHS through linkage and exome sequencing in multigenerational kindreds. (PMID:22529292)

Initial genetic studies identified heterozygous PIEZO1 mutations in two multigenerational HX kindreds with complete cosegregation across all affected members, confirming dominant inheritance. Further analysis of a large pedigree and 11 unrelated DHS cases revealed three novel missense mutations and one recurrent C-terminal duplication in PIEZO1, establishing it as the major gene for DHS. (PMID:23695678)

Subsequent cohort analyses have reinforced the genetic association: in 123 hereditary stomatocytosis patients, PIEZO1 mutations were found in 47% of pedigrees, predominantly in nonpore and pore domains; and a retrospective series of 126 subjects documented PIEZO1 variants in 49 families, including 12 novel missense alleles. (PMID:30187933; PMID:30655378)

The variant spectrum exceeds 30 distinct alleles, mainly missense changes clustered in the C‐terminal pore region. Recurrent gain‐of‐function mutations such as c.6674T>G (p.Met2225Arg) have been reported in multiple unrelated families, underscoring mutational hotspots. (PMID:22529292; PMID:23695678)

Functional assays demonstrate that DHS‐associated PIEZO1 mutations slow channel inactivation and increase cation permeability, leading to erythrocyte dehydration. Electrophysiological studies in heterologous systems and patient red cells confirm a gain‐of‐function mechanism, while proteomic profiling reveals dysregulated ion transport and vesicle pathways consistent with chronic hemolysis. (PMID:23487776; PMID:36595486)

Overall, definitive genetic and functional evidence over more than a decade supports PIEZO1 gain‐of‐function mutations as the cause of autosomal dominant DHS. Genetic testing for PIEZO1 variants informs diagnostic workflows and guides management, including avoidance of splenectomy due to thrombotic risk. Key take-home: PIEZO1 mutational analysis is clinically essential for diagnosing and managing dehydrated hereditary stomatocytosis.

References

• Blood • 2012 • Mutations in the mechanotransduction protein PIEZO1 are associated with hereditary xerocytosis. PMID:22529292
• Nature communications • 2013 • Dehydrated hereditary stomatocytosis linked to gain-of-function mutations in mechanically activated PIEZO1 ion channels. PMID:23695678
• Proceedings of the National Academy of Sciences of the United States of America • 2013 • Xerocytosis is caused by mutations that alter the kinetics of the mechanosensitive channel PIEZO1. PMID:23487776
• American journal of hematology • 2018 • Genotype-phenotype correlation and risk stratification in a cohort of 123 hereditary stomatocytosis patients. PMID:30187933
• Haematologica • 2019 • Clinical and biological features in PIEZO1-hereditary xerocytosis and Gardos channelopathy: a retrospective series of 126 patients. PMID:30655378
• Blood advances • 2023 • Proteome alterations in erythrocytes with PIEZO1 gain-of-function mutations. PMID:36595486

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