TWO NOVEL MISSENSE MUTATIONS IN PIEZO1 IN SIX PATIENTS WITH DEHYDRATED HEREDITARY STOMATOCYTOSIS

ABSSUB-4482

Background: Hereditary stomatocytosis is a rare cause of hereditary hemolytic anemia. It concerns a heterogeneous group of disorders characterized by altered cellular hydration state. Dehydrated hereditary stomatocytosis (DHSt), also known as hereditary xerocytosis, is among this group of so called channelopathies of the red blood cells. It is an autosomal dominant disorder and recently mutations in PIEZO1 have been linked to this disease. PIEZO1 encodes a mechanosensitive ion channel protein. As result of mutation DHSt red blood cells exhibit impaired potassium and sodium balance leading to their dehydration. DHSt is characterized by mild to moderate hemolytic anemia and may present with pseudohyperkalemia and perinatal edema.

Aims: We performed DNA sequence analysis of PIEZO1 in six DHSt patients from three unrelated families. The diagnosis DHSt was established using osmotic gradient ektacytometry by Laser-assisted Optical Rotational Cell Analyzer (LoRRca, Mechatronics, Hoorn, The Netherlands) showing a characteristic left shift of the curve.

Results: DNA analysis revealed four different mutations in PIEZO1, two of which were novel (Table, novel mutations in bold).

Table. PIEZO1 genotypes of the six DHSt patients

The two novel mutations c.6262C>G and c.1276C>T both segregated with disease in the respective families. Furthermore, both Arg2088 and Cys426 concern residues that are highly conserved in PIEZO1 (http://genome.ucsc.edu/). Moreover, in silico analysis by Polyphen and SIFT predict that substitution with, respectively, glycine and arginine is not tolerated. Interestingly, the p.(Cys426Arg) mutation is the most N-terminal mutation identified so far in PIEZO1.

In addition to the p.Arg2088Gly mutation, a second mutation was identified in patient 2 from family 1. This mutation predicts the deletion of one out of four lysine residues between amino acids 2166-2169 and was previously reported in association with DHSt. The mutation was inherited from the patient’s mother who was completely asymptomatic and hematologically normal. Notably, the clinical phenotype of patient 1 was more severe when compared to that of his brother (patient 3) and father (patient 1).

Summary/Conclusion: Molecular characterization of six DHSt patients from three unrelated families revealed four mutations inPIEZO1. Two of these mutations have not been previously reported: p.(Arg2088Gly) and p.(Cys426Arg). Our findings further establish the correlation between mutations in PIEZO1 and DHSt, a rare channel disorder of the red blood cell.

Keywords: None

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