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Mechanosensitive Piezo1 ion channel protein (PIEZO1 gene): update and extended mutation analysis of hereditary xerocytosis in India

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Abstract

Hereditary xerocytosis (HX), also known as dehydrated stomatocytosis (DHSt) is a dominantly inherited genetic disorder exhibiting red cell membrane dehydration caused by the loss of the monovalent cation K+ and water. Variants in mechanosensitive Piezo ionic channels of the PIEZO1 gene are the primary cause of HX. We have utilized high throughput and highly precise next-generation sequencing (NGS) to make a diagnosis and examine the genotype-phenotype relationship in inflexible HX cases. Seven unrelated patients with unexplained hemolytic anemia were scrutinized with a panel probing 8000 genes related to congenital anemia. Targeted next-generation sequencing identified 8 missense variants in the PIEZO1 gene in 7 unrelated Indian patients. Three of the 8 variants are novel (c.1795G > C, c.2915G > A, c.7372 T > C) and the remaining five (c.4082A > G, c.6829C > A, c.7374C > G, c.7381G > A, c.7483_7488dup) are previously reported. The variants have been validated by Sanger sequencing. One patient with autosomal dominant mutation (c.7372 T > C) is associated with iron refractory iron deficiency anemia. Of the 7 patients, one has HX in combination with a novel homozygous variant (c.994G > A) in the PKLR gene causing PK deficiency resulting in severe clinical manifestations with phenotypic variability. In silico prediction using bioinformatics tools were used to study the possible damaging effects of the novel variants. Structural-functional analysis of the novel variants was investigated by molecular modeling software (PyMOL and Swiss PDB). These results encompass the heterogeneous behavior of mechano-sensitive Piezo1 protein observed in HX patients in India. Moreover, NGS imparted a subtle, economical, and quick tool for understanding the genetic cause of undiagnosed cases of congenital hemolytic anemia. NGS grants a potential technology integrating clinical history together with molecular report profiting in such patients and their families.

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Acknowledgments

We would like to thank patients and family members for their cooperation and participation in this study. This study was performed with the support of the Indian Council of Medical Research New Delhi, and the Department of Science and Technology (DST) New Delhi for financial support.

Funding

This study was performed with the financial support of the Indian Council of Medical Research New Delhi and the Department of Science and Technology New Delhi (SERB Project No. EEQ/2017/000115).

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  1. Department of Hematogenetics, ICMR-National Institute of Immunohematology, KEM Hospital Campus, Parel, Mumbai, 40012, India

    Tejashree Anil More, Rashmi Dongerdiye, Rati Devendra, Prashant P. Warang & Prabhakar S. Kedar

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Correspondence to Prabhakar S. Kedar.

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The study protocol was approved by the Institutional Ethical Committee of ICMR-National Institute of Immunohematology, Mumbai. Informed consent was obtained from the parents or guardians of patients prior to enrollment in the study. All procedures performed in our study were in accordance with the 1964 Helsinki declaration.

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More, T.A., Dongerdiye, R., Devendra, R. et al. Mechanosensitive Piezo1 ion channel protein (PIEZO1 gene): update and extended mutation analysis of hereditary xerocytosis in India. Ann Hematol 99, 715–727 (2020). https://doi.org/10.1007/s00277-020-03955-1

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