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dc.contributor.authorEllard, Sian
dc.date.accessioned2020-02-19T15:59:26Z
dc.date.available2020-02-19T15:59:26Z
dc.date.issued2019-12
dc.identifier.citationMann N [et al]. CAKUT and autonomic dysfunction caused by acetylcholine receptor mutations. American Journal of Human Genetics. 2019 105(6) 1286-1293en_US
dc.identifier.pmid31708116
dc.identifier.doi10.1016/j.ajhg.2019.10.004
dc.identifier.urihttps://rde.dspace-express.com/handle/11287/621236
dc.description.abstractCongenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney disease in the first three decades of life, and in utero obstruction to urine flow is a frequent cause of secondary upper urinary tract malformations. Here, using whole-exome sequencing, we identified three different biallelic mutations in CHRNA3, which encodes the α3 subunit of the nicotinic acetylcholine receptor, in five affected individuals from three unrelated families with functional lower urinary tract obstruction and secondary CAKUT. Four individuals from two families have additional dysautonomic features, including impaired pupillary light reflexes. Functional studies in vitro demonstrated that the mutant nicotinic acetylcholine receptors were unable to generate current following stimulation with acetylcholine. Moreover, the truncating mutations p.Thr337Asnfs∗81 and p.Ser340∗ led to impaired plasma membrane localization of CHRNA3. Although the importance of acetylcholine signaling in normal bladder function has been recognized, we demonstrate for the first time that mutations in CHRNA3 can cause bladder dysfunction, urinary tract malformations, and dysautonomia. These data point to a pathophysiologic sequence by which monogenic mutations in genes that regulate bladder innervation may secondarily cause CAKUT.en_US
dc.language.isoenen_US
dc.publisherCell Pressen_US
dc.relation.urlhttps://linkinghub.elsevier.com/retrieve/pii/S0002-9297(19)30392-1en_US
dc.subjectWessex Classification Subject Headings::Oncology. Pathology.::Geneticsen_US
dc.titleCAKUT and autonomic dysfunction caused by acetylcholine receptor mutationsen_US
dc.typeJournal Articleen_US
dc.identifier.journalAmerican Journal of Human Geneticsen_US
dc.identifier.pmcidPMC6904809
dc.type.versionPublisheden_US


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