Defects in TCIRG1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive osteopetrosis
Defects in TCIRG1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive osteopetrosis
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DOI：
10.1038/77131
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发表时间：
2000-07-01
期刊：
影响因子：
30.8
通讯作者：
Villa, A
中科院分区：
文献类型：
--
作者：
Frattini, A;Orchard, PJ;Villa, A
骨质疏松包括一组遗传性疾病，其中骨吸收不足是由破骨细胞功能障碍引起的。尽管分子缺陷已被描述为许多骨质疏松症的动物模型。导致大多数严重的人类形式的疾病（婴儿恶性骨质疏松症）的基因是未知的。婴儿恶性常染色体隐性骨性硬化症（MIM 259700）是一种严重的骨病，通常在生命的第一个十年内致命。在常染色体隐性骨质疏松症患者中，破骨细胞的数量正常或升高(1)，这表明这种缺陷不在于破骨细胞的分化，而在于一个参与成熟破骨细胞功能的基因。一些小鼠突变体的破骨细胞数量减少。这表明该缺陷直接干扰破骨细胞分化（2,3）。在其他突变体中，似乎是破骨细胞的功能受到了影响，因为它们显示出正常或增加的无功能破骨细胞数量（2,4-6）。在这里，我们发现编码空泡质子泵破骨细胞特异性116-kD亚基的TCIRG1在诊断为婴儿恶性骨质疏松症的9例患者中有5例发生突变。我们的数据表明，TCIRG1突变是人类常染色体隐性骨质疏松症的常见原因。
Osteopetrosis includes a group of inherited diseases in which inadequate bone resorption is caused by osteoclast dysfunction. Although molecular defects have been described for many animal models of osteopetrosis. the gene responsible for most cases of the severe human form of the disease (infantile malignant osteopetrosis) is unknown. Infantile malignant autosomal recessive osteopetrosis (MIM 259700) is a severe bone disease with a fatal outcome, generally within the first decade of life. Osteoclasts are present in normal or elevated numbers in individuals affected by autosomal recessive osteopetrosis(1), suggesting that the defect is not in osteoclast differentiation, but in a gene involved in the functional capacity of mature osteoclasts. Some of the mouse mutants have a decreased number of osteoclasts. which suggests that the defect directly interferes with osteoclast differentiation(2,3). In other mutants, it is the function of the osteoclast that seems to be affected, as they show normal or elevated numbers of non-functioning osteoclasts(2,4-6). Here we show that TCIRG1, encoding the osteoclast-specific 116-kD subunit of the vacuolar proton pump, is mutated in five of nine patients with a diagnosis of infantile malignant osteopetrosis. Our data indicate that mutations in TCIRG1 are a frequent cause of autosomal recessive osteopetrosis in humans.