SNX10 Mutations Define a Subgroup of Human Autosomal Recessive Osteopetrosis With Variable Clinical Severity
SNX10 Mutations Define a Subgroup of Human Autosomal Recessive Osteopetrosis With Variable Clinical Severity
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DOI：
10.1002/jbmr.1849
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发表时间：
2013-05-01
影响因子：
6.2
通讯作者：
Sobacchi, Cristina
中科院分区：
文献类型：
--
作者：
Pangrazio, Alessandra;Fasth, Anders;Sobacchi, Cristina
人常染色体隐性骨硬化症（ARO）是一种遗传异质性疾病，由破骨细胞减少骨吸收引起。在2000年，我们发现编码质子泵亚基（V-ATP酶）的TCIRG 1基因突变与一半以上的ARO病例有关。从那时起，又有五个基因被证明参与了该病的发病机制，剩下大约25%的病例与基因型无关。最近，在3个巴勒斯坦血统的近亲家庭中发现了分类连接蛋白10（SNX 10）基因的突变，其产物被认为与质子泵相互作用，从而在以前未分类的患者中增加了一个新的候选基因。在这里，我们报告了9个新的突变，在这个基因的14例ARO患者从12个无关的家庭不同的地理来源。有趣的是，我们定义的分子缺陷，在三个案件的Vasterbottenian骨硬化症，命名为瑞典省的发病率较高的疾病已被报道。在我们来自世界各地的310多名患者的队列中，SNX 10依赖性ARO占病例的4%，其频率与NF-B配体受体激活剂（RANKL）、NF-B受体激活剂（RANK）和骨硬化相关跨膜蛋白1（OSTM 1）依赖性亚群相当。虽然临床表现的严重程度相对可变，但骨似乎是唯一受影响的组织，并且造血干细胞移植（HSCT）几乎可以完全挽救缺损。这些结果证实了SNX 10基因参与人类ARO，并确定了一个新的子集，与TCIRG 1依赖性病例相比，具有相对有利的预后。进一步的分析将有助于更好地理解SNX 10在破骨细胞生理学中的作用，并验证这种蛋白质是否可以被认为是选择性抗吸收治疗的新靶点。(c)2013年美国骨矿物质研究学会。
Human Autosomal Recessive Osteopetrosis (ARO) is a genetically heterogeneous disorder caused by reduced bone resorption by osteoclasts. In 2000, we found that mutations in the TCIRG1 gene encoding for a subunit of the proton pump (V-ATPase) are responsible for more than one-half of ARO cases. Since then, five additional genes have been demonstrated to be involved in the pathogenesis of the disease, leaving approximately 25% of cases that could not be associated with a genotype. Very recently, a mutation in the sorting nexin 10 (SNX10) gene, whose product is suggested to interact with the proton pump, has been found in 3 consanguineous families of Palestinian origin, thus adding a new candidate gene in patients not previously classified. Here we report the identification of 9 novel mutations in this gene in 14 ARO patients from 12 unrelated families of different geographic origin. Interestingly, we define the molecular defect in three cases of Vasterbottenian osteopetrosis, named for the Swedish Province where a higher incidence of the disease has been reported. In our cohort of more than 310 patients from all over the world, SNX10-dependent ARO constitutes 4% of the cases, with a frequency comparable to the receptor activator of NF-B ligand (RANKL), receptor activator of NF-B (RANK) and osteopetrosis-associated transmembrane protein 1 (OSTM1)-dependent subsets. Although the clinical presentation is relatively variable in severity, bone seems to be the only affected tissue and the defect can be almost completely rescued by hematopoietic stem cell transplantation (HSCT). These results confirm the involvement of the SNX10 gene in human ARO and identify a new subset with a relatively favorable prognosis as compared to TCIRG1-dependent cases. Further analyses will help to better understand the role of SNX10 in osteoclast physiology and verify whether this protein might be considered a new target for selective antiresorptive therapies. (c) 2013 American Society for Bone and Mineral Research.