Macia Maxence S, Halbritter Jan, Delous Marion, Bredrup Cecilie, Gutter Arthur, Filhol Emilie, Mellgren Anne E C, Leh Sabine, Bizet Albane, Braun Daniela A, Gee Heon Y, Silbermann Flora, Henry Charline, Krug Pauline, Bole-Feysot Christine, Nitschké Patrick, Joly Dominique, Nicoud Philippe, Paget André, Haugland Heidi, Brackmann Damien, Ahmet Nayir, Sandford Richard, Cengiz Nurcan, Knappskog Per M, Boman Helge, Linghu Bolan, Yang Fan, Oakeley Edward J, Saint Mézard Pierre, Sailer Andreas W, Johansson Stefan, Rødahl Eyvind, Saunier Sophie, Hildebrandt Friedhelm, Benmerah Alexandre
INSERM, UMR-1163, Laboratory of Inherited Kidney Diseases, 75015 Paris, France; Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France.
Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Division of Nephrology, Department of Internal Medicine, University Clinic Leipzig, 04103 Leipzig, Germany.
Am J Hum Genet. 2017 Feb 2;100(2):323-333. doi: 10.1016/j.ajhg.2016.12.011. Epub 2017 Jan 12.
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 Mapkbp1 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.
肾单位肾痨（NPH）是一种常染色体隐性遗传性肾小管间质性肾炎，是生命最初三十年中遗传性终末期肾病的最常见病因。由于大多数NPH基因产物（NPHP）在初级纤毛中发挥作用，NPH被归类为纤毛病。我们在来自五个家庭的八名个体中鉴定出一个候选基因的突变，这些个体表现为迟发性NPH并伴有大量肾纤维化。该基因编码MAPKBP1，一种对JNK信号传导特征了解甚少的支架蛋白。免疫荧光分析表明，MAPKBP1不存在于初级纤毛中，且患病个体的成纤维细胞未表现出纤毛发生缺陷，这表明MAPKBP1可能代表了一个新的NPHP家族，不参与与纤毛相关的功能。相反，在有丝分裂早期，MAPKBP1被募集到有丝分裂纺锤体极（MSP），在那里它与其旁系同源物WDR62共定位，而WDR62在MSP中起关键作用。检测到的突变损害了MAPKBP1向MSP的募集和/或其与JNK2或WDR62的相互作用。此外，我们发现患病个体的成纤维细胞以及在小鼠细胞系中敲低Mapkbp1后，DNA损伤反应信号增强，这是一种先前与NPH相关的表型。总之，我们鉴定出MAPKBP1中的突变是青少年或迟发性以及不依赖纤毛的NPH的遗传病因。
