Jinks Robert N, Puffenberger Erik G, Baple Emma, Harding Brian, Crino Peter, Fogo Agnes B, Wenger Olivia, Xin Baozhong, Koehler Alanna E, McGlincy Madeleine H, Provencher Margaret M, Smith Jeffrey D, Tran Linh, Al Turki Saeed, Chioza Barry A, Cross Harold, Harlalka Gaurav V, Hurles Matthew E, Maroofian Reza, Heaps Adam D, Morton Mary C, Stempak Lisa, Hildebrandt Friedhelm, Sadowski Carolin E, Zaritsky Joshua, Campellone Kenneth, Morton D Holmes, Wang Heng, Crosby Andrew, Strauss Kevin A
1 Department of Biology and Biological Foundations of Behaviour Program, Franklin and Marshall College, Lancaster, PA 17604, USA
1 Department of Biology and Biological Foundations of Behaviour Program, Franklin and Marshall College, Lancaster, PA 17604, USA 2 Clinic for Special Children, Strasburg, PA 17579, USA.
Brain. 2015 Aug;138(Pt 8):2173-90. doi: 10.1093/brain/awv153. Epub 2015 Jun 11.
We describe a novel nephrocerebellar syndrome on the Galloway-Mowat syndrome spectrum among 30 children (ages 1.0 to 28 years) from diverse Amish demes. Children with nephrocerebellar syndrome had progressive microcephaly, visual impairment, stagnant psychomotor development, abnormal extrapyramidal movements and nephrosis. Fourteen died between ages 2.7 and 28 years, typically from renal failure. Post-mortem studies revealed (i) micrencephaly without polymicrogyria or heterotopia; (ii) atrophic cerebellar hemispheres with stunted folia, profound granule cell depletion, Bergmann gliosis, and signs of Purkinje cell deafferentation; (iii) selective striatal cholinergic interneuron loss; and (iv) optic atrophy with delamination of the lateral geniculate nuclei. Renal tissue showed focal and segmental glomerulosclerosis and extensive effacement and microvillus transformation of podocyte foot processes. Nephrocerebellar syndrome mapped to 700 kb on chromosome 15, which contained a single novel homozygous frameshift variant (WDR73 c.888delT; p.Phe296Leufs26). WDR73 protein is expressed in human cerebral cortex, hippocampus, and cultured embryonic kidney cells. It is concentrated at mitotic microtubules and interacts with α-, β-, and γ-tubulin, heat shock proteins 70 and 90 (HSP-70; HSP-90), and the carbamoyl phosphate synthetase 2/aspartate transcarbamylase/dihydroorotase multi-enzyme complex. Recombinant WDR73 p.Phe296Leufs26 and p.Arg256Profs18 proteins are truncated, unstable, and show increased interaction with α- and β-tubulin and HSP-70/HSP-90. Fibroblasts from patients homozygous for WDR73 p.Phe296Leufs26 proliferate poorly in primary culture and senesce early. Our data suggest that in humans, WDR73 interacts with mitotic microtubules to regulate cell cycle progression, proliferation and survival in brain and kidney. We extend the Galloway-Mowat syndrome spectrum with the first description of diencephalic and striatal neuropathology.
我们描述了一种在来自不同阿米什族群的30名儿童（年龄1.0至28岁）中发现的加洛韦 - 莫瓦特综合征谱系上的新型肾小脑综合征。患有肾小脑综合征的儿童有进行性小头畸形、视力障碍、精神运动发育停滞、锥体外系运动异常和肾病。14名儿童在2.7至28岁之间死亡，通常死于肾衰竭。尸检研究显示：（i）脑过小但无多小脑回或异位；（ii）小脑半球萎缩，小叶发育不良，颗粒细胞严重缺失，伯格曼胶质细胞增生，以及浦肯野细胞脱传入的迹象；（iii）选择性纹状体胆碱能中间神经元丢失；（iv）视神经萎缩伴外侧膝状体分层。肾组织显示局灶性和节段性肾小球硬化以及足细胞足突广泛消失和微绒毛转化。肾小脑综合征定位于15号染色体上700 kb的区域，该区域包含一个单一的新型纯合移码变体（WDR73 c.888delT；p.Phe296Leufs26）。WDR73蛋白在人类大脑皮层、海马体和培养的胚胎肾细胞中表达。它集中在有丝分裂微管上，并与α -、β - 和γ - 微管蛋白、热休克蛋白70和90（HSP - 70；HSP - 90）以及氨基甲酰磷酸合成酶2/天冬氨酸转氨甲酰酶/二氢乳清酸酶多酶复合物相互作用。重组WDR73 p.Phe296Leufs26和p.Arg256Profs18蛋白被截断、不稳定，并显示与α - 和β - 微管蛋白以及HSP - 70/HSP - 90的相互作用增加。WDR73 p.Phe296Leufs26纯合患者的成纤维细胞在原代培养中增殖不良且衰老较早。我们的数据表明，在人类中，WDR73与有丝分裂微管相互作用，以调节大脑和肾脏中的细胞周期进程、增殖和存活。我们首次描述了间脑和纹状体神经病理学，从而扩展了加洛韦 - 莫瓦特综合征谱系。
