Pub Date : 2016-09-04DOI: 10.12974/2311-8687.2016.04.02.1
Jing Chen, A. T. van der Ven, J. Newman, A. Vivante, Nina Mann, H. Aitkenhead, S. Shril, Hadas Ityel, J. Schulz, J. Schmidt, E. Widmeier, O. Gileadi, F. Costantini, Shifaan Thowfeequ, R. Wenger, S. Bauer, R. S. Lee, Weining Lu, Maike Getwan, Michael M. Kaminski, S. Lienkamp, R. Lifton, V. Tasic, E. Kehinde, F. Hildebrandt
Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common reason for chronic kidney disease in children. Although more than 30 monogenic causes have been implicated in isolated forms of human CAKUT so far, the vast majority remains elusive. To identify novel monogenic causes of CAKUT we applied homozygosity mapping, together with whole exome sequencing, in a patient from consanguineous descent with isolated CAKUT. We identified a homozygous missense mutation (p.Arg415His) of the Ets Translocation Variant Gene 4 (ETV4). The transcription factor ETV4 is a downstream target of the GDNF/RET signaling pathway that plays a crucial role in kidney development. We show by means of electrophoretic mobility shift assay that the Arg415His mutant causes loss of the DNA binding affinity of ETV4 and fails to activate transcription in a cell-based luciferase reporter assay. We furthermore investigated the impact of the mutant protein on cell migration rate. Unlike wildtype ETV4, the Arg415His mutant failed to rescue cell migration defects observed in two ETV4 knock-down cell-lines. We therefore identified and functionally characterized a recessive mutation in ETV4 in a human patient with CAKUT. We hypothesize that the pathomechanism of this mutation could be via loss of the transcriptional function of ETV4, and a resulting abrogation of GDNF/RET/ETV4 signaling pathway.
{"title":"ETV4 Mutation in a Patient with Congenital Anomalies of the Kidney and Urinary Tract","authors":"Jing Chen, A. T. van der Ven, J. Newman, A. Vivante, Nina Mann, H. Aitkenhead, S. Shril, Hadas Ityel, J. Schulz, J. Schmidt, E. Widmeier, O. Gileadi, F. Costantini, Shifaan Thowfeequ, R. Wenger, S. Bauer, R. S. Lee, Weining Lu, Maike Getwan, Michael M. Kaminski, S. Lienkamp, R. Lifton, V. Tasic, E. Kehinde, F. Hildebrandt","doi":"10.12974/2311-8687.2016.04.02.1","DOIUrl":"https://doi.org/10.12974/2311-8687.2016.04.02.1","url":null,"abstract":"Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common reason for chronic kidney disease in children. Although more than 30 monogenic causes have been implicated in isolated forms of human CAKUT so far, the vast majority remains elusive. To identify novel monogenic causes of CAKUT we applied homozygosity mapping, together with whole exome sequencing, in a patient from consanguineous descent with isolated CAKUT. We identified a homozygous missense mutation (p.Arg415His) of the Ets Translocation Variant Gene 4 (ETV4). The transcription factor ETV4 is a downstream target of the GDNF/RET signaling pathway that plays a crucial role in kidney development. We show by means of electrophoretic mobility shift assay that the Arg415His mutant causes loss of the DNA binding affinity of ETV4 and fails to activate transcription in a cell-based luciferase reporter assay. We furthermore investigated the impact of the mutant protein on cell migration rate. Unlike wildtype ETV4, the Arg415His mutant failed to rescue cell migration defects observed in two ETV4 knock-down cell-lines. We therefore identified and functionally characterized a recessive mutation in ETV4 in a human patient with CAKUT. We hypothesize that the pathomechanism of this mutation could be via loss of the transcriptional function of ETV4, and a resulting abrogation of GDNF/RET/ETV4 signaling pathway. ","PeriodicalId":91713,"journal":{"name":"International journal of pediatrics and child health","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66337112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2015-08-01DOI: 10.12974/2311-8687.2015.03.01.2
Sofie Halmø Hürdum, Guicheng Zhang, S. Khoo, Joelene A. Bizzintino, Kimberley Franks, K. Lindsay, A. Keil, D. Cox, J. Goldblatt, Y. Bochkov, J. Gern, C. Ulrik, P. N. Souëf, I. Laing
INTRODUCTION It is unclear if children with a rhinovirus (RV)-induced wheezing exacerbation are more susceptible to viruses longitudinally, and whether a parental history of asthma and/or allergy impacts their susceptibility. The objective of this study was to determine if RV, RV-A and RV-C related wheezing exacerbations in children were associated with prior or subsequent viral detections and investigate the role of parental history of asthma and allergy. MATERIALS AND METHODS Children presenting to hospital with acute wheeze were prospectively recruited and tested for respiratory viruses. Data on viruses detected in other respiratory samples (May 1997 to December 2012) were collected from hospital microbiology records and additional RV testing was performed on stored hospital respiratory samples (September 2009 to December 2012). A positive parental history was defined as either parent with self-reported asthma and/or allergy. RESULTS At recruitment, RV was detected in 69.2% of samples from children with an acute wheezing episode (n=373, 0-16 years of age), with RV-C the most common virus (65.5%). Children with a history of parental asthma and/or allergy and RV at recruitment had a 14-fold increased incidence rate ratio (IRR) of subsequent RV detection (IRR 14.0, 95% CI 1.9-104.1; p=0.01) compared with children without RV at recruitment. Children without this parental history had a reduced incident rate ratio for samples assessed during this time (IRR 0.5, 95% CI 0.3-0.9; p=0.03). CONCLUSION Children with a parental history of asthma and/or allergy may become more susceptible to recurrent symptomatic RV infections.
目前尚不清楚鼻病毒(RV)诱导的喘息加重患儿是否更容易感染病毒，以及父母的哮喘和/或过敏史是否会影响他们的易感性。本研究的目的是确定RV、RV- a和RV- c相关的儿童喘息加重是否与先前或随后的病毒检测有关，并调查父母哮喘和过敏史的作用。材料与方法前瞻性地招募急性喘息患儿并进行呼吸道病毒检测。从医院微生物记录中收集了其他呼吸道样本中检测到的病毒数据(1997年5月至2012年12月)，并对储存的医院呼吸道样本进行了额外的RV检测(2009年9月至2012年12月)。阳性的父母史定义为父母中有一方自我报告有哮喘和/或过敏。结果在急性喘息发作患儿(n=373, 0 ~ 16岁)中，有69.2%的样本检出RV，其中RV- c病毒最常见(65.5%)。在招募时父母有哮喘和/或过敏史和RV的儿童，随后发现RV的发病率比(IRR)增加了14倍(IRR 14.0, 95% CI 1.9-104.1;p=0.01)。在此期间评估的样本中，没有这种父母史的儿童的事故率较低(IRR 0.5, 95% CI 0.3-0.9;p = 0.03)。结论父母有哮喘和/或过敏史的儿童更容易发生复发性症状RV感染。
{"title":"Recurrent rhinovirus detections in children following a rhinovirus-induced wheezing exacerbation: A retrospective study.","authors":"Sofie Halmø Hürdum, Guicheng Zhang, S. Khoo, Joelene A. Bizzintino, Kimberley Franks, K. Lindsay, A. Keil, D. Cox, J. Goldblatt, Y. Bochkov, J. Gern, C. Ulrik, P. N. Souëf, I. Laing","doi":"10.12974/2311-8687.2015.03.01.2","DOIUrl":"https://doi.org/10.12974/2311-8687.2015.03.01.2","url":null,"abstract":"INTRODUCTION\u0000It is unclear if children with a rhinovirus (RV)-induced wheezing exacerbation are more susceptible to viruses longitudinally, and whether a parental history of asthma and/or allergy impacts their susceptibility. The objective of this study was to determine if RV, RV-A and RV-C related wheezing exacerbations in children were associated with prior or subsequent viral detections and investigate the role of parental history of asthma and allergy.\u0000\u0000\u0000MATERIALS AND METHODS\u0000Children presenting to hospital with acute wheeze were prospectively recruited and tested for respiratory viruses. Data on viruses detected in other respiratory samples (May 1997 to December 2012) were collected from hospital microbiology records and additional RV testing was performed on stored hospital respiratory samples (September 2009 to December 2012). A positive parental history was defined as either parent with self-reported asthma and/or allergy.\u0000\u0000\u0000RESULTS\u0000At recruitment, RV was detected in 69.2% of samples from children with an acute wheezing episode (n=373, 0-16 years of age), with RV-C the most common virus (65.5%). Children with a history of parental asthma and/or allergy and RV at recruitment had a 14-fold increased incidence rate ratio (IRR) of subsequent RV detection (IRR 14.0, 95% CI 1.9-104.1; p=0.01) compared with children without RV at recruitment. Children without this parental history had a reduced incident rate ratio for samples assessed during this time (IRR 0.5, 95% CI 0.3-0.9; p=0.03).\u0000\u0000\u0000CONCLUSION\u0000Children with a parental history of asthma and/or allergy may become more susceptible to recurrent symptomatic RV infections.","PeriodicalId":91713,"journal":{"name":"International journal of pediatrics and child health","volume":"3 1 1","pages":"10-18"},"PeriodicalIF":0.0,"publicationDate":"2015-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66337506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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