CAKUT and Autonomic Dysfunction Caused by Acetylcholine Receptor Mutations.

Area of Science:

• Genetics
• Nephrology
• Developmental Biology

Background:

• Congenital anomalies of the kidney and urinary tract (CAKUT) are a leading cause of chronic kidney disease.
• In utero urinary obstruction frequently leads to secondary upper urinary tract malformations.

Purpose of the Study:

• To investigate the genetic basis of functional lower urinary tract obstruction and secondary CAKUT.
• To identify novel genes associated with bladder dysfunction and related congenital anomalies.

Main Methods:

• Whole-exome sequencing was performed on affected individuals from three families.
• Functional in vitro studies assessed the impact of identified mutations on nicotinic acetylcholine receptor function and localization.

Main Results:

• Three distinct biallelic mutations in CHRNA3, encoding the nicotinic acetylcholine receptor alpha-3 subunit, were identified in five individuals.
• Mutant receptors showed impaired acetylcholine-stimulated current generation and reduced plasma membrane localization.
• Affected individuals exhibited lower urinary tract obstruction, secondary CAKUT, and in some cases, dysautonomia.

Conclusions:

• Mutations in CHRNA3 are a novel cause of bladder dysfunction, leading to secondary CAKUT and dysautonomia.
• This study highlights the critical role of acetylcholine signaling in bladder innervation and development.
• Monogenic mutations affecting bladder innervation can secondarily cause CAKUT, revealing a new pathophysiological pathway.