Analysis of extracellular mRNA in human urine reveals splice variant biomarkers of muscular dystrophies.
Analysis of extracellular mRNA in human urine reveals splice variant biomarkers of muscular dystrophies.
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DOI：
10.1038/s41467-018-06206-0
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发表时间：
2018-09-25
影响因子：
16.6
通讯作者：
Wheeler TM
中科院分区：
文献类型：
--
作者：
Antoury L;Hu N;Balaj L;Das S;Georghiou S;Darras B;Clark T;Breakefield XO;Wheeler TM
尿液中含有泌尿生殖系统肿瘤的细胞外RNA （exRNA）标记物。然而，尿液中遗传物质识别全身性疾病的能力尚不清楚。在这里，我们将人类尿液中的exRNA剪接产物描述为两种最常见形式的肌肉营养不良，肌强直性营养不良（DM）和杜氏肌营养不良（DMD）的生物标志物来源。利用训练集、RT-PCR、微滴数字PCR和主成分回归，我们鉴定出10个在DM1型患者（DM1）尿液exRNA中拼接不同的转录本，与未受影响或疾病对照相比，形成了一个复合生物标志物，并开发了一个预测模型，在我们的独立验证集中是100%准确的。尿液中也含有突变特异性DMD mrna，证实了反义寡核苷酸药物eteplirsen的外显子跳跃活性。我们的研究结果表明，尿液mRNA剪接变异可以用于监测全身性疾病，而对泌尿道的临床影响很小或没有。肌强直性营养不良患者需要进行有创性肌肉活检以监测疾病进展和对治疗的反应。在这里，作者表明，人类尿液中的细胞外rna可以作为生物标志物，用于区分患者与未受影响的对照组，并监测服用eteplirsen的杜氏肌营养不良患者的外显子跳变。
Urine contains extracellular RNA (exRNA) markers of urogenital cancers. However, the capacity of genetic material in urine to identify systemic diseases is unknown. Here we describe exRNA splice products in human urine as a source of biomarkers for the two most common forms of muscular dystrophies, myotonic dystrophy (DM) and Duchenne muscular dystrophy (DMD). Using a training set, RT-PCR, droplet digital PCR, and principal component regression, we identify ten transcripts that are spliced differently in urine exRNA from patients with DM type 1 (DM1) as compared to unaffected or disease controls, form a composite biomarker, and develop a predictive model that is 100% accurate in our independent validation set. Urine also contains mutation-specific DMD mRNAs that confirm exon-skipping activity of the antisense oligonucleotide drug eteplirsen. Our results establish that urine mRNA splice variants can be used to monitor systemic diseases with minimal or no clinical effect on the urinary tract. Patients with myotonic dystrophy need to undergo invasive muscle biopsies to monitor disease progression and response to therapy. Here, the authors show that extracellular RNAs in human urine can be used as biomarkers to differentiate patients from unaffected controls, and to monitor exon skipping in patients with Duchenne muscular dystrophy taking the drug eteplirsen.
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影响因子：
--
作者：
Matsuzaki K;Fujita K;Jingushi K;Kawashima A;Ujike T;Nagahara A;Ueda Y;Tanigawa G;Yoshioka I;Ueda K;Hanayama R;Uemura M;Miyagawa Y;Tsujikawa K;Nonomura N
通讯作者：
Nonomura N
影响因子：
14.9
作者：
Imbeaud S;Graudens E;Boulanger V;Barlet X;Zaborski P;Eveno E;Mueller O;Schroeder A;Auffray C
通讯作者：
Auffray C
影响因子：
4.6
作者：
Bouge, Anne-Laure;Murauer, Eva;Tuffery-Giraud, Sylvie
通讯作者：
Tuffery-Giraud, Sylvie
影响因子：
3.8
作者：
Khan S;Bennit HF;Turay D;Perez M;Mirshahidi S;Yuan Y;Wall NR
通讯作者：
Wall NR
影响因子：
11.2
作者：
Nakamori, Masayuki;Sobczak, Krzysztof;Puwanant, Araya;Welle, Steve;Eichinger, Katy;Pandya, Shree;Dekdebrun, Jeannne;Heatwole, Chad R.;McDermott, Michael P.;Chen, Tian;Cline, Melissa;Tawil, Rabi;Osborne, Robert J.;Wheeler, Thurman M.;Swanson, Maurice S.;Moxley, Richard T., III;Thornton, Charles A.
通讯作者：
Thornton, Charles A.