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Am J Hum Genet. 2019 Dec 5;105(6):1286-1293. doi: 10.1016/j.ajhg.2019.10.004. Epub 2019 Nov 7.

CAKUT and Autonomic Dysfunction Caused by Acetylcholine Receptor Mutations.

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Department of Pediatrics, Boston Children's Hospital, Boston, MA 02115, USA.
Department of Molecular Medicine, Cornell University, Ithaca, NY 14853, USA.
Departments of Neuroscience and Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Department of Clinical Genetics, St. Michael's Hospital, University Hospital's Bristol NHS Foundation Trust, Bristol BS2 8EG, UK.
Pediatric Nephrology Center of Excellence and Pediatric Department, Faculty of Medicine, King Abdulaziz University, Jeddah 21859, Kingdom of Saudi Arabia.
Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter EX2 5DW, UK.
Medical Faculty Skopje, University Children's Hospital, Skopje 1000, Macedonia.
Department of Urology, Boston Children's Hospital, Boston, MA 02115, USA.
Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Division of Nephrology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA.
Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA; Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY 10065, USA.
Institute of Human Genetics, University of Bonn, Bonn 53127, Germany Department of Neonatology and Pediatric Intensive Care, Children's Hospital, University of Bonn, Bonn 53127, Germany.
Department of Pediatrics, Boston Children's Hospital, Boston, MA 02115, USA. Electronic address:


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.


CAKUT; dysautonomia; genetics; kidney; neurogenic bladder

[Available on 2020-06-05]

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