SNX10 gene mutation leading to osteopetrosis with dysfunctional osteoclasts.
SNX10 gene mutation leading to osteopetrosis with dysfunctional osteoclasts.
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DOI：
10.1038/s41598-017-02533-2
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发表时间：
2017-06-07
影响因子：
4.6
通讯作者：
Lerner UH
中科院分区：
文献类型：
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作者：
Stattin EL;Henning P;Klar J;McDermott E;Stecksen-Blicks C;Sandström PE;Kellgren TG;Rydén P;Hallmans G;Lönnerholm T;Ameur A;Helfrich MH;Coxon FP;Dahl N;Wikström J;Lerner UH
常染色体隐性遗传性石骨症（ARO）是一种异质性疾病，其特征是骨吸收缺陷导致骨密度增加。我们已经研究了9个人与中间形式的ARO，从县的Västerbotten在北方瑞典。所有受影响的人都在婴儿早期发病，伴有视神经萎缩，4例患者在诊断时存在贫血。扁桃体突出、枕骨大孔狭窄及严重的颌骨骨髓炎是常见的临床特征。通过桑格测序验证的全外显子组测序鉴定了编码分选连接蛋白10的SNX 10基因中的剪接位点突变c.212 + 1 G > T。对患者SNX 10转录本的序列分析显示，内含子4中的隐蔽剪接位点活化，导致移码和过早终止（p.S66Nfs * 15）。单倍型分析显示，所有病例均起源于单一突变事件，突变年龄估计约为950岁。从患者外周血中分离的破骨细胞祖细胞的功能分析显示，用核因子κ-B配体受体激活剂（RANKL）刺激导致大的、多核破骨细胞的稳健形成，其产生密封区;然而，这些破骨细胞表现出有缺陷的皱褶边界，并且无法在体外吸收骨。
Autosomal recessive osteopetrosis (ARO) is a heterogeneous disorder, characterized by defective osteoclastic resorption of bone that results in increased bone density. We have studied nine individuals with an intermediate form of ARO, from the county of Västerbotten in Northern Sweden. All afflicted individuals had an onset in early infancy with optic atrophy, and in four patients anemia was present at diagnosis. Tonsillar herniation, foramen magnum stenosis, and severe osteomyelitis of the jaw were common clinical features. Whole exome sequencing, verified by Sanger sequencing, identified a splice site mutation c.212 + 1 G > T in the SNX10 gene encoding sorting nexin 10. Sequence analysis of the SNX10 transcript in patients revealed activation of a cryptic splice site in intron 4 resulting in a frame shift and a premature stop (p.S66Nfs * 15). Haplotype analysis showed that all cases originated from a single mutational event, and the age of the mutation was estimated to be approximately 950 years. Functional analysis of osteoclast progenitors isolated from peripheral blood of patients revealed that stimulation with receptor activator of nuclear factor kappa-B ligand (RANKL) resulted in a robust formation of large, multinucleated osteoclasts which generated sealing zones; however these osteoclasts exhibited defective ruffled borders and were unable to resorb bone in vitro.