ADCK4 mutations promote steroid-resistant nephrotic syndrome through CoQ10 biosynthesis disruption
ADCK4 mutations promote steroid-resistant nephrotic syndrome through CoQ10 biosynthesis disruption
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DOI：
10.1172/jci69000
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发表时间：
2013-12-01
影响因子：
15.9
通讯作者：
Hildebrandt, Friedhelm
中科院分区：
文献类型：
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作者：
Ashraf, Shazia;Gee, Heon Yung;Hildebrandt, Friedhelm
激素耐药型肾病综合征（SRNS）单基因病因的发现，进一步加深了对该病发病机制的认识。在这里，使用纯合性作图和全人类外显子组重测序的组合，我们确定了在aarF域包含激酶4（ADCK 4）基因突变的15个人与SRNS从8个无关的家庭。ADCK 4与ADCK 3高度相似，ADCK 3已被证明参与辅酶Q（10）（CoQ（10））生物合成。ADCK4突变导致COQ降低（10）。从SRNS个体和转化的淋巴母细胞分离的细胞中，线粒体呼吸酶活性降低。在斑马鱼和果蝇中敲除adck4重演肾病综合征相关表型此外，ADCK 4在肾小球足细胞中表达，并在大鼠肾脏和培养的人足细胞中部分定位于足细胞线粒体和足突。在人类足细胞中，ADCK 4与辅酶Q（10）生物合成途径的成员相互作用，包括与SRNS和辅酶Q 7相关的辅酶Q 6。足细胞中ADCK 4的敲低导致迁移减少，这被CoQ（10）逆转。有趣的是，一名携带纯合子ADCK4移码突变的SRNS患者在CoQ（10）治疗后部分缓解。这些数据表明，ADCK 4或其他参与辅酶Q生物合成的基因突变的SRNS患者可能可以用辅酶Q治疗。
Identification of single-gene causes of steroid-resistant nephrotic syndrome (SRNS) has furthered the understanding of the pathogenesis of this disease. Here, using a combination of homozygosity mapping and whole human exome resequencing, we identified mutations in the aarF domain containing kinase 4 (ADCK4) gene in 15 individuals with SRNS from 8 unrelated families. ADCK4 was highly similar to ADCK3, which has been shown to participate in coenzyme Q(10) (CoQ(10)) biosynthesis. Mutations in ADCK4 resulted in reduced COQ(10). levels and reduced mitochondrial respiratory enzyme activity in cells isolated from individuals with SRNS and transformed lymphoblasts. Knockdown of adck4 in zebrafish and Drosophila recapitulated nephrotic syndrome-associated phenotypes. Furthermore, ADCK4 was expressed in glomerular podocytes and partially localized to podocyte mitochondria and foot processes in rat kidneys and cultured human podocytes. In human podocytes, ADCK4 interacted with members of the CoQ(10) biosynthesis pathway, including COQ6, which has been linked with SRNS and COQ7. Knockdown of ADCK4 in podocytes resulted in decreased migration, which was reversed by CoQ(10) addition. Interestingly, a patient with SRNS with a homozygous ADCK4 frameshift mutation had partial remission following CoQ(10) treatment. These data indicate that individuals with SRNS with mutations in ADCK4 or other genes that participate in CoQ(10) biosynthesis may be treatable with CoQ(10).