MYO1E mutations and childhood familial focal segmental glomerulosclerosis.
MYO1E mutations and childhood familial focal segmental glomerulosclerosis.
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DOI：
10.1056/nejmoa1101273
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发表时间：
2011-07-28
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影响因子：
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通讯作者：
PodoNet Consortium
中科院分区：
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作者：
Mele C;Iatropoulos P;Donadelli R;Calabria A;Maranta R;Cassis P;Buelli S;Tomasoni S;Piras R;Krendel M;Bettoni S;Morigi M;Delledonne M;Pecoraro C;Abbate I;Capobianchi MR;Hildebrandt F;Otto E;Schaefer F;Macciardi F;Ozaltin F;Emre S;Ibsirlioglu T;Benigni A;Remuzzi G;Noris M;PodoNet Consortium
局灶节段性肾小球硬化（FSGS）是一种肾病，表现为肾病综合征，通常对糖皮质激素耐药，50-70%的患者进展为终末期肾病。家族性FSGS的遗传学研究表明，它是一种足细胞疾病，足细胞是肾小球滤过屏障的主要成分。然而，超过一半的原发性FSGS的分子原因是未知的，有效的治疗一直难以捉摸。我们进行了全基因组连锁分析，然后在一个常染色体隐性遗传FSGS家族的阳性连锁区进行高通量测序，并对52名无关FSGS患者的新发现基因进行了测序。在人肾活检和培养的足细胞中进行免疫组织化学。进行体外表达研究以表征鉴定的突变的功能后果。在MYO 1 E中发现了两个突变（A159 P和Y 695 X），编码非肌肉I类肌球蛋白，肌球蛋白1 E（Myo 1 E），在两个独立的家系中与FSGS分离。患者为突变纯合子，对糖皮质激素耐药。电镜下可见肾小球基底膜增厚、结构紊乱。Myo 1 E的正常表达在体内对照人肾活检和体外肾小球足细胞中均有记录。转染研究显示A159 P-Myo 1 E突变体的亚细胞定位和功能异常。Y 695 X突变导致钙调蛋白结合和Myo 1 E尾部结构域的丧失。MYO 1 E突变导致儿童期类固醇耐药FSGS这些数据支持Myo 1 E在足细胞功能中的作用以及肾小球选择性渗透屏障的完整性。
Focal segmental glomerulosclerosis (FSGS) is a kidney disease that presents with nephrotic syndrome and is often resistant to glucocorticosteroids and progresses to end-stage kidney disease in 50–70% of patients. Genetic studies in familial FSGS indicate that it is a disease of the podocytes, major components of the glomerular filtration barrier. However the molecular cause of over half of primary FSGS is unknown, and effective treatments have been elusive. We performed whole-genome linkage analysis followed by high-throughput sequencing of the positive linkage area in a family with autosomal recessive FSGS and sequenced a newly discovered gene in 52 unrelated FSGS patients. Immunohistochemistry was performed in human kidney biopsies and cultured podocytes. Expression studies in vitro were performed to characterize the functional consequences of the mutations identified. Two mutations (A159P and Y695X) in MYO1E, encoding the non-muscle class I myosin, myosin 1E (Myo1E), which segregated with FSGS in two independent pedigrees were identified. Patients were homozygous for the mutations and were resistant to glucocorticosteroids. Electron microscopy showed thickening and disorganization of the glomerular basement membrane. Normal expression of Myo1E was documented in control human kidney biopsies in vivo and in glomerular podocytes in vitro. Transfection studies revealed abnormal subcellular localization and function of A159P-Myo1E mutant. The Y695X mutation causes loss of calmodulin binding and the tail domains of Myo1E. MYO1E mutations lead to childhood onset steroid-resistant FSGS. These data support a role of Myo1E in podocyte function and the consequent integrity of the glomerular permselectivity barrier.