Mutations in MAPKBP1 Cause Juvenile or Late-Onset Cilia-Independent Nephronophthisis
Mutations in MAPKBP1 Cause Juvenile or Late-Onset Cilia-Independent Nephronophthisis
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DOI：
10.1016/j.ajhg.2016.12.011
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发表时间：
2017-02-02
影响因子：
9.8
通讯作者：
Benmerah, Alexandre
中科院分区：
文献类型：
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作者：
Macia, Maxence S.;Halbritter, Jan;Benmerah, Alexandre
肾单位病变(NPH)是一种常染色体隐性遗传性肾小管间质肾炎，是出生后30年内遗传性终末期肾病最常见的病因。由于大多数NPH基因产物(NPHP)在原发纤毛中起作用，NPH被归类为纤毛疾病。我们确定了来自5个表现为晚发性NPH伴大量肾脏纤维化的家系的8个个体的候选基因突变。该基因编码MAPKBP1，这是一种特性不佳的JNK信号支架蛋白。免疫荧光分析表明，MAPKBP1不存在于初级纤毛组织中，并且患者的成纤维细胞不存在纤毛发生缺陷，这表明MAPKBP1可能代表了一个新的NPHP家族，该家族不参与纤毛相关功能。相反，MAPKBP1在有丝分裂的早期阶段被招募到有丝分裂的纺锤体极(MSP)，在那里它与在MSP起关键作用的WDR62共定位。检测到的突变影响了MAPKBP1向MSP的招募和/或其与JNK2或WDR62的相互作用。此外，我们还发现，在受影响个体的成纤维细胞中，以及在小鼠细胞系中Mapkbpl基因被敲除后，DNA损伤反应信号增加，这是以前与NPH相关的一种表型。总之，我们确定MAPKBP1突变是青少年或晚发型和纤毛非依赖性NPH的遗传原因。
Nephronophthisis (NPH), an autosomal-recessive tubulointerstitial nephritis, is the most common cause of hereditary end-stage renal disease in the first three decades of life. Since most NPH gene products (NPHP) function at the primary cilium, NPH is classified as a ciliopathy. We identified mutations in a candidate gene in eight individuals from five families presenting late-onset NPH with massive renal fibrosis. This gene encodes MAPKBP1, a poorly characterized scaffolding protein for JNK signaling. Immunofluorescence analyses showed that MAPKBP1 is not present at the primary cilium and that fibroblasts from affected individuals did not display ciliogenesis defects, indicating that MAPKBP1 may represent a new family of NPHP not involved in cilia-associated functions. Instead, MAPKBP1 is recruited to mitotic spindle poles (MSPs) during the early phases of mitosis where it colocalizes with its paralog WDR62, which plays a key role at MSP. Detected mutations compromise recruitment of MAPKBP1 to the MSP and/or its interaction with JNK2 or WDR62. Additionally, we show increased DNA damage response signaling in fibroblasts from affected individuals and upon knockdown of Mapkbpl in murine cell lines, a phenotype previously associated with NPH. In conclusion, we identified mutations in MAPKBP1 as a genetic cause of juvenile or late-onset and cilia-independent NPH.