Osteoclast rich osteopetrosis due to defects in TCIRG1 gene.

Bone Pub Date : 2022-08-01 DOI:10.2139/ssrn.4138979
Valentina Capo, M. Abinun, A. Villa
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引用次数: 4

Abstract

The discovery that mutations in TCIRG1 (also known as Atp6i) gene are responsible for the majority of autosomal recessive osteopetrosis (ARO) forms in humans heralded a new era for comprehension of this heterogeneous rare bone disease. TCIRG1 gene encodes the a3 subunit, an essential isoform of the vacuolar ATPase proton pump involved in the acidification of the resorption lacuna and in secretory lysosome trafficking. The gene defects lead to inefficient bone resorption by unfunctional osteoclasts which are seen in abundance on bone marrow biopsy, delineating this form of ARO as 'osteoclast-rich'. Patients usually present in early childhood with features of extramedullary haematopoiesis (hepatosplenomegaly, anaemia, thrombocytopenia) due to bone marrow fibrosis, and cranial nerve encroachment (blindness in particular). Impaired gastric calcium uptake due to high pH causes the co-occurrence of rickets, described as "osteopetrorickets". Osteoclast dysfunction leads to early death if untreated and allogeneic haematopoietic stem cell transplantation is the treatment of choice. Combined studies in patients and mouse models carrying spontaneous (the oc/oc mouse) or targeted disruption of Atp6i (TCIRG1) gene have been instrumental for the insight into disease pathogenesis and for the development of novel cellular therapies exploiting gene correction.
TCIRG1基因缺陷引起的富破骨细胞骨质疏松症。
TCIRG1(也称为Atp6i)基因突变是人类大多数常染色体隐性遗传性骨病(ARO)的原因,这一发现预示着理解这种异质性罕见骨病的新时代。TCIRG1基因编码a3亚基,这是液泡ATP酶质子泵的一种重要异构体,参与吸收腔隙的酸化和分泌溶酶体的运输。基因缺陷导致非功能性破骨细胞的骨吸收效率低下,在骨髓活检中可以看到大量的破骨细胞,将这种形式的ARO描述为“富含破骨细胞”。患者通常在儿童早期出现骨髓纤维化引起的髓外造血(肝脾肿大、贫血、血小板减少)和颅神经侵犯(尤其是失明)。高pH值导致胃钙摄取受损,导致软骨病的同时发生,被称为“骨质疏松性软骨病”。如果不治疗,破骨细胞功能障碍会导致早期死亡,选择异基因造血干细胞移植治疗。在携带Atp6i(TCIRG1)基因的自发(oc/oc小鼠)或靶向破坏的患者和小鼠模型中进行的联合研究有助于深入了解疾病的发病机制,并有助于开发利用基因校正的新型细胞疗法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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