CAKUT and Autonomic Dysfunction Caused by Acetylcholine Receptor Mutations

Nina Mann, Franziska Kause, Erik K. Henze, Anant Gharpure, Shirlee Shril, Dervla M. Connaughton, Makiko Nakayama, Verena Klämbt, Amar J. Majmundar, Chen Han W. Wu, Caroline M. Kolvenbach, Rufeng Dai, Jing Chen, Amelie T. van der Ven, Hadas Ityel, Madeleine J. Tooley, Jameela A. Kari, Lucy Bownass, Sherif El Desoky, Elisa De FrancoMohamed Shalaby, Velibor Tasic, Stuart B. Bauer, Richard S. Lee, Jonathan M. Beckel, Weiqun Yu, Shrikant M. Mane, Richard P. Lifton, Heiko Reutter, Sian Ellard, Ryan E. Hibbs, Toshimitsu Kawate, Friedhelm Hildebrandt

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


Congenital 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.Thr337Asnfs81 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.

Original languageEnglish (US)
Pages (from-to)1286-1293
Number of pages8
JournalAmerican Journal of Human Genetics
Issue number6
StatePublished - Dec 5 2019


  • dysautonomia
  • genetics
  • kidney
  • neurogenic bladder

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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