Traditional and targeted exome sequencing reveals common, rare and novel functional deleterious variants in RET-signaling complex in a cohort of living US patients with urinary tract malformations.
Traditional and targeted exome sequencing reveals common, rare and novel functional deleterious variants in RET-signaling complex in a cohort of living US patients with urinary tract malformations.
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DOI：
10.1007/s00439-012-1181-3
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发表时间：
2012-11
期刊：
影响因子：
5.3
通讯作者：
Jain, Sanjay
中科院分区：
文献类型：
--
作者：
Chatterjee, Rajshekhar;Ramos, Enrique;Hoffman, Mary;VanWinkle, Jessica;Martin, Daniel R.;Davis, Thomas K.;Hoshi, Masato;Hmiel, Stanley P.;Beck, Anne;Hruska, Keith;Coplen, Doug;Liapis, Helen;Mitra, Robi;Druley, Todd;Austin, Paul;Jain, Sanjay
神经胶质细胞系来源的神经营养因子(GDNF)-RET受体酪氨酸激酶和SPRY1 （RET抑制因子）的信号传导对早期尿路发育至关重要。小鼠中GDNF、RET和SPRY1突变等位基因的单个或组合导致肾脏畸形，类似于人类的先天性肾脏或尿路异常（CAKUT），不同于完全GDNF或RET缺失小鼠的肾脏发育表型。我们对122名不相关的活着的CAKUT患者的GDNF、SPRY1和RET进行了测序，以发现导致CAKUT的有害突变。在6例不相关的患者中发现了新的或罕见的GDNF或RET有害突变。一个具有重复收集系统的家族有一个新的突变，RETR831Q，显示GDNF依赖性MAPK活性显著降低。两名RET-G691S多态性患者携带额外的罕见非同义变体GDNF-R93W和RET-R982C。RET-G691S/R982C双基因型患者存在多种缺陷，包括肾发育不良、计尿器和隐睾。这两种突变的存在是影响RET活性所必需的。靶向全外显子组和下一代测序显示，该患者RET共受体GFRα1中存在新的有害突变G443D。系谱分析表明，GFRα1突变遗传自未受影响的母亲，RET突变遗传自未受影响的父亲。我们的研究表明，5%的活着的CAKUT患者在GDNF-GFRα1-RET通路中存在有害的罕见变异或新突变。我们提供了证据，证明在同一途径中，有害的罕见和常见变异在基因中共存，作为导致CAKUT的原因，并发现了与RET途径相关的新表型。
Signaling by the glial cell line-derived neurotrophic factor (GDNF)-RET receptor tyrosine kinase and SPRY1, a RET repressor, is essential for early urinary tract development. Individual or a combination of GDNF, RET and SPRY1 mutant alleles in mice cause renal malformations reminiscent of congenital anomalies of the kidney or urinary tract (CAKUT) in humans and distinct from renal agenesis phenotype in complete GDNF or RET null mice. We sequenced GDNF, SPRY1 and RET in 122 unrelated living CAKUT patients to discover deleterious mutations that cause CAKUT. Novel or rare deleterious mutations in GDNF or RET were found in 6 unrelated patients. A family with duplicated collecting system had a novel mutation, RETR831Q, which showed markedly decreased GDNF dependent MAPK activity. Two patients with RET-G691S polymorphism harbored additional rare non-synonymous variants GDNF-R93W and RET-R982C. The patient with double RET-G691S/R982C genotype had multiple defects including renal dysplasia, megaureters and cryptorchidism. Presence of both mutations were necessary to affect RET activity. Targeted whole exome and next-generation sequencing revealed a novel deleterious mutation G443D in GFRα1, the co-receptor for RET, in this patient. Pedigree analysis indicated that the GFRα1 mutation was inherited from the unaffected mother and the RET mutations from the unaffected father. Our studies indicate that 5% of living CAKUT patients harbor deleterious rare variants or novel mutations in GDNF-GFRα1-RET pathway. We provide evidence for the coexistence of deleterious rare and common variants in genes in the same pathway as a cause of CAKUT and discovered novel phenotypes associated with the RET pathway.
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影响因子：
3.7
作者：
Ghosh, S.;Krux, F.;Borkhardt, A.
通讯作者：
Borkhardt, A.
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
64.8
作者：
Moore, MW;Klein, RD;Rosenthal, A
通讯作者：
Rosenthal, A
影响因子：
4
作者：
Jeanpierre, Cecile;Mace, Guillaume;Salomon, Remi
通讯作者：
Salomon, Remi
影响因子：
12.4
作者：
Encinas, M.;Rozen, E. J.;Johnson, E. M., Jr.
通讯作者：
Johnson, E. M., Jr.