Mutations in the leukemia inhibitory factor receptor (LIFR) gene and Lifr deficiency cause urinary tract malformations
Mutations in the leukemia inhibitory factor receptor (LIFR) gene and Lifr deficiency cause urinary tract malformations
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DOI：
10.1093/hmg/ddx086
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发表时间：
2017-05-01
影响因子：
3.5
通讯作者：
Weber, Ruthild G.
中科院分区：
文献类型：
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作者：
Kosfeld, Anne;Brand, Frank;Weber, Ruthild G.
先天性肾脏和泌尿道异常（CAKUT）是儿童慢性肾脏疾病最常见的原因。由于CAKUT是一种遗传异质性疾病，并且大多数病例在遗传上无法解释，因此我们旨在确定新的CAKUT致病基因。使用全外显子组测序和基于trio的从头分析，我们确定了一种新的杂合从头移码变异白血病抑制因子受体（LIFR）基因，导致不稳定的mRNA在患者提出双边CAKUT和需要肾移植在一岁。LIFR编码由IL-6家族细胞因子利用的跨膜受体，主要由白血病抑制因子（LIF）利用。对另外121例严重CAKUT患者的突变分析产生了两种罕见的杂合LIFR错义变体，预测其在3例无关患者中具有致病性。LIFR突变体显示半衰期和细胞膜定位减少，导致LIF刺激的STAT 3磷酸化减少。LIFR在人胎儿肾和人输尿管中显示高表达，并且在发育中的小鼠泌尿生殖系统中也表达。Lifr基因敲除小鼠表现出尿路畸形，包括肾盂积水、输尿管积水、输尿管异位，并且一致地，输尿管腔减少和肌肉肥大，与携带LIFR变体的患者中观察到的表型相似。此外，在所有Lifr（-/-）小鼠和携带LIFR移码突变的患者中检测到一种隐睾症。总而言之，我们在3.3%的CAKUT患者中证明了杂合的新的或罕见的LIFR突变，并提供了证据表明，Lifr缺乏和失活LIFR突变导致小鼠和人类泌尿生殖道高度相似的异常。
Congenital anomalies of the kidneys and urinary tract (CAKUT) are the most common cause of chronic kidney disease in children. As CAKUT is a genetically heterogeneous disorder and most cases are genetically unexplained, we aimed to identify new CAKUT causing genes. Using whole-exome sequencing and trio-based de novo analysis, we identified a novel heterozygous de novo frameshift variant in the leukemia inhibitory factor receptor (LIFR) gene causing instability of the mRNA in a patient presenting with bilateral CAKUT and requiring kidney transplantation at one year of age. LIFR encodes a transmembrane receptor utilized by IL-6 family cytokines, mainly by the leukemia inhibitory factor (LIF). Mutational analysis of 121 further patients with severe CAKUT yielded two rare heterozygous LIFR missense variants predicted to be pathogenic in three unrelated patients. LIFR mutants showed decreased half-life and cell membrane localization resulting in reduced LIF-stimulated STAT3 phosphorylation. LIFR showed high expression in human fetal kidney and the human ureter, and was also expressed in the developing murine urogenital system. Lifr knockout mice displayed urinary tract malformations including hydronephrosis, hydroureter, ureter ectopia, and, consistently, reduced ureteral lumen and muscular hypertrophy, similar to the phenotypes observed in patients carrying LIFR variants. Additionally, a form of cryptorchidism was detected in all Lifr(-/-) mice and the patient carrying the LIFR frameshift mutation. Altogether, we demonstrate heterozygous novel or rare LIFR mutations in 3.3% of CAKUT patients, and provide evidence that Lifr deficiency and deactivating LIFR mutations cause highly similar anomalies of the urogenital tract in mice and humans.