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Mechanosensitive Piezo1 ion channel protein (PIEZO1 gene): update and extended mutation analysis of hereditary xerocytosis in India.
Annals of Hematology ( IF 3.5 ) Pub Date : 2020-02-28 , DOI: 10.1007/s00277-020-03955-1
Tejashree Anil More 1 , Rashmi Dongerdiye 1 , Rati Devendra 1 , Prashant P Warang 1 , Prabhakar S Kedar 1
Affiliation  

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.

中文翻译:

机械敏感的Piezo1离子通道蛋白(PIEZO1基因):印度遗传性干细胞增多症的更新和扩展突变分析。

遗传性干细胞增多症(HX),也称为脱水造血干细胞增多症(DHSt),是一种遗传性显性遗传疾病,表现出由于单价阳离子K +和水的损失而引起的红细胞膜脱水。PIEZO1基因的机械敏感压电离子通道的变异是引起HX的主要原因。我们已经利用高通量和高度精确的下一代测序(NGS)进行诊断,并检查了不易弯曲的HX病例中的基因型与表型的关系。七名与原因不明的溶血性贫血无关的不相关患者接受了与先天性贫血相关的8000个基因的探查。有针对性的下一代测序技术在7名印度无关患者中鉴定出PIEZO1基因的8个错义变体。8个变体中的三个是新颖的(c.1795G> C,c.2915G> A,c.7372 T> C),其余五个(c。先前已报告4082A> G,c.6829C> A,c.7374C> G,c.7381G> A,c.7483_7488dup)。变异体已经通过Sanger测序验证。一名具有常染色体显性遗传突变(c.7372 T> C)的患者与难治性铁缺乏性贫血有关。在这7例患者中,有1例HX与PKLR基因中新的纯合变异体(c.994G> A)结合,导致PK缺乏,导致严重的临床表现和表型变异。使用生物信息学工具进行计算机预测,用于研究新变体的可能破坏作用。通过分子建模软件(PyMOL和Swiss PDB)研究了新变体的结构功能分析。这些结果包括在印度HX患者中观察到的机械敏感Piezo1蛋白的异质性行为。此外,NGS为了解先天性溶血性贫血未诊断病例的遗传原因提供了一种微妙,经济且快速的工具。NGS授予了一种潜在技术,可将此类患者及其家庭的临床历史与分子报告相结合。
更新日期:2020-02-28
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