Whole-exome sequencing identifies mutations in the nucleoside transporter gene SLC29A3 in dysosteosclerosis, a form of osteopetrosis
Whole-exome sequencing identifies mutations in the nucleoside transporter gene SLC29A3 in dysosteosclerosis, a form of osteopetrosis
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DOI：
10.1093/hmg/dds326
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发表时间：
2012-11-15
影响因子：
3.5
通讯作者：
Lee, Brendan H.
中科院分区：
文献类型：
--
作者：
Campeau, Philippe M.;Lu, James T.;Lee, Brendan H.
骨质疏松症（DSS）是一种骨硬化症，其特征是存在皮肤表现，如红紫色黄斑萎缩、扁平脊椎和干骺端骨质疏松，骨干增宽相对透亮。在组织病理学水平上，当疾病出现时，破骨细胞缺乏。在2例DSS患者中，我们通过全外显子组测序鉴定了SLC29A3的纯合或复合杂合错义突变。该基因编码一种核苷转运蛋白，突变引起组织细胞病淋巴结病附加综合征，一组很少或没有骨骼受累的疾病。这种转运蛋白对小鼠的溶酶体功能至关重要。我们证明了Slc29a3在小鼠体内破骨细胞中的表达。在DSS患者的单核细胞中，我们观察到破骨细胞分化和功能降低（钙表面脱矿）。我们的报告强调了这种核苷转运蛋白功能障碍的多形性后果，并重要地提出了一种新的机制，控制破骨细胞的分化和功能。
Dysosteosclerosis (DSS) is the form of osteopetrosis distinguished by the presence of skin findings such as red-violet macular atrophy, platyspondyly and metaphyseal osteosclerosis with relative radiolucency of widened diaphyses. At the histopathological level, there is a paucity of osteoclasts when the disease presents. In two patients with DSS, we identified homozygous or compound heterozygous missense mutations in SLC29A3 by whole-exome sequencing. This gene encodes a nucleoside transporter, mutations in which cause histiocytosislymphadenopathy plus syndrome, a group of conditions with little or no skeletal involvement. This transporter is essential for lysosomal function in mice. We demonstrate the expression of Slc29a3 in mouse osteoclasts in vivo. In monocytes from patients with DSS, we observed reduced osteoclast differentiation and function (demineralization of calcium surface). Our report highlights the pleomorphic consequences of dysfunction of this nucleoside transporter, and importantly suggests a new mechanism for the control of osteoclast differentiation and function.