Mutations in the a3 subunit of the vacuolar H+-ATPase cause infantile malignant osteopetrosis
Mutations in the a3 subunit of the vacuolar H+-ATPase cause infantile malignant osteopetrosis
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DOI：
10.1093/hmg/9.13.2059
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发表时间：
2000-08-12
影响因子：
3.5
通讯作者：
Kubisch, C
中科院分区：
文献类型：
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作者：
Kornak, U;Schulz, A;Kubisch, C
虽然已知几种小鼠突变体的严重骨石化症的基因缺陷，但人类婴儿恶性隐性骨石化症的潜在基因仍然难以捉摸。骨石化症被认为是由破骨细胞功能缺陷引起的。这些细胞在紧密密封的细胞外室中降解骨材料，细胞外室被液泡（V）型H+-ATP酶酸化。编码酸化机制组分的基因是石骨症的候选基因。在10例婴儿恶性石骨症患者中的5例中，我们现在证明了OC 116的5种不同突变，OC 116是编码破骨细胞V-ATP酶α 3亚基的基因。两个独立的患者是纯合子突变，预测功能完全丧失严重截断蛋白。通过影响剪接位点，另一个纯合突变删除了N-末端内的14个氨基酸，其与质子泵的其他亚基相互作用。另一方面，在4例患者中未发现突变，1例来自血缘家族的患者在OC 116位点未显示纯合性，这表明至少一个不同基因的突变可能是石骨症的基础。我们的工作表明，编码质子泵α 3亚基的基因突变是婴儿石骨症的一个相当常见的原因，并表明这种疾病是遗传异质性的。
Although the gene defects for several mouse mutants with severe osteopetrosis are known, the genes underlying human infantile malignant recessive osteopetrosis remain elusive, Osteopetrosis is thought to be caused by a defect in osteoclast function. These cells degrade bone material in a tightly sealed extracellular compartment that is acidified by a vacuolar (V)-type H+-ATPase. Genes encoding components of the acidification machinery are candidate genes for osteopetrosis, In five of ten patients with infantile malignant osteopetrosis, we now demonstrate five different mutations in OC116, the gene encoding the a3 subunit of the V-ATPase from osteoclasts. Two independent patients were homozygous for mutations that predict a total loss of function by severely truncating the protein. By affecting a splice site, another homozygous mutation deletes 14 amino acids within the N-terminus, which interacts with other subunits of the proton pump. On the other hand, in four patients no mutations were found, and one patient from a consanguineous family did not show homozygosity at the OC116 locus, suggesting that mutations in at least one different gene may underlie osteopetrosis, Our work shows that mutations in the gene encoding the a3 subunit of the proton pump are a rather common cause of infantile osteopetrosis and suggests that this disease is genetically heterogeneous.