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Case Reports
. 2018 Mar;103(3):e94-e97.
doi: 10.3324/haematol.2017.180687. Epub 2017 Nov 30.

PIEZO1-R1864H rare variant accounts for a genetic phenotype-modifier role in dehydrated hereditary stomatocytosis

Immacolata Andolfo  1   2 , Francesco Manna  3   2 , Gianluca De Rosa  3   2 , Barbara Eleni Rosato  3   2 , Antonella Gambale  3   2 , Giovanna Tomaiuolo  2   4 , Antonio Carciati  2   4 , Roberta Marra  3   2 , Lucia De Franceschi  5 , Achille Iolascon  3   2 , Roberta Russo  3   2
Affiliations
Case Reports

PIEZO1-R1864H rare variant accounts for a genetic phenotype-modifier role in dehydrated hereditary stomatocytosis

Immacolata Andolfo et al. Haematologica. 2018 Mar.
No abstract available

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Figures

Figure 1.
Figure 1.
Partial pedigree of the two families analyzed and ektacytometry analyses. (A) Inheritance pattern of PIEZO1-E2492_L2493dup mutation in Family A. The proband A-I1 is indicated by an arrow. (B) Inheritance pattern of PIEZO1-E2492_L2493dup mutation in Family B. The proband B-II1 is indicated by an arrow. (C) The red cell deformability index (DI) was measured as a function of increasing osmolarity red cells from Family A patients I1, I2, III2, IV2 and from internal healthy controls of the same family (I2 and II3). Values are means ± Standard Error of Mean (SEM) of two independent experiments. (D) DI was measured as a function of increasing osmolarity red cells from family B patients I1, 2II, from unaffected subject of the same family (I2), and from a healthy control. Values are means ± SEM of two independent experiments.
Figure 2.
Figure 2.
Modifier effect of PIEZO1 R1864H on cation flux. (A) PIEZO1 mRNA levels in HEK-293 cells over-expressing human PIEZO1-WT, PIEZO1-E2492_L2493dup, PIEZO1-R1864H, and PIEZO1 double mutant E2492_L2493dup + R1864H. Values are means ± Standard Error of Mean (SEM) of three independent experiments. *P<0.05 WT/WT vs. WT/E2492_L2493dup+R1864H; WT/E2492_L2493dup vs. WT/E2492_L2493dup+R1864H; WT/R1864H vs. WT/E2492_L2493dup+R1864H. (B) (Top) Immunoblot showing PIEZO1 protein expression in cells over-expressing human PIEZO1-WT and mutants. β-actin is loading control. (Bottom) Densitometric analysis of three separate Western blotting with similar results. (C) Extracellular K+ content in culture medium from HEK-293 cells over-expressing PIEZO1-WT and mutants, as described in (A). Open circles indicate empty vector (EV); gray circles indicate wild-type (WT); black circles indicate PIEZO1-E2492_L2493dup; gray triangles indicate PIEZO1-R1864H; black rhomboids indicate PIEZO1 double mutant E2492_L2493dup+R1864H (P<0.0001 all mutants by ANOVA test; ***P<0.0001 E2492_L2493dup vs. E2492_L2493dup+R1864H by Bonferroni post-hoc test; **P<0.05 E2492_L2493dup vs. R1864H by Bonferroni post-hoc test). Values are depicted for each replicate (n=5). (D) Cell Rb+ content of cells over-expressing PIEZO1-WT and mutants, as described in (C). Open circles indicate EV; gray circles indicate WT; black circles indicate PIEZO1-E2492_L2493dup; gray triangles indicate PIEZO1-R1864H; black rhomboids indicate PIEZO1 double mutant E2492_L2493dup+R1864H (P<0.0001 all mutants by ANOVA test; **P<0.05 E2492_L2493dup vs. R1864H by Bonferroni post-hoc test; E2492_L2493dup vs. E2492_L2493dup+R1864H by Bonferroni post-hoc test). Values are depicted for each replicate (n=5). ns: not significant.
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References

    1. Andolfo I, Russo R, Gambale A, Iolascon A. New insights on hereditary erythrocyte membrane defects. Haematologica. 2016;101(11):1284–1294. - PMC - PubMed
    1. Rapetti-Mauss R, Lacoste C, Picard V, et al. A mutation in the Gardos channel is associated with hereditary xerocytosis. Blood. 2015;126(11):1273–1280. - PubMed
    1. Andolfo I, Russo R, Manna F, et al. Novel Gardos channel mutations linked to dehydrated hereditary stomatocytosis (xerocytosis). Am J Hematol. 2015;90(10):921–926. - PubMed
    1. Glogowska E, Lezon-Geyda K, Maksimova Y, Schulz VP, Gallagher PG. Mutations in the Gardos channel (KCNN4) are associated with hereditary xerocytosis. Blood. 2015;126(11):1281–1284. - PMC - PubMed
    1. Andolfo I, Alper SL, De Franceschi L, et al. Multiple clinical forms of dehydrated hereditary stomatocytosis arise from mutations in PIEZO1. Blood. 2013;121(19):3925–3935. - PubMed

Supplementary concepts

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