Neurogenic bladder is caused by disruption of neuronal pathways regulating bladder relaxation and contraction. In severe cases, neurogenic bladder can lead to vesicoureteral reflux, hydroureter, and chronic kidney disease. These complications overlap with manifestations of congenital anomalies of the kidney and urinary tract (CAKUT). To identify novel monogenic causes of neurogenic bladder, we applied exome sequencing (ES) to our cohort of families with CAKUT. By ES, we have identified a homozygous missense variant (p.Gln184Arg) in CHRM5 (cholinergic receptor, muscarinic, 5) in a patient with neurogenic bladder and secondary complications of CAKUT. CHRM5 codes for a seven transmembrane-spanning G-protein-coupled muscarinic acetylcholine receptor. CHRM5 is shown to be expressed in murine and human bladder walls and is reported to cause bladder overactivity in Chrm5 knockout mice. We investigated CHRM5 as a potential novel candidate gene for neurogenic bladder with secondary complications of CAKUT. CHRM5 is similar to the cholinergic bladder neuron receptor CHRNA3, which Mann et al. published as the first monogenic cause of neurogenic bladder. However, functional in vitro studies did not reveal evidence to strengthen the status as a candidate gene. Discovering additional families with CHRM5 variants could help to further assess the genes' candidate status.
American journal of medical genetics. Part A. 2023 May 22 [Epub ahead of print]
Sophia Schneider, Luca Schierbaum, Wessel A C Burger, Steve Seltzsam, Chunyan Wang, Bixia Zheng, Chen-Han Wilfred Wu, Makiko Nakayama, Dervla M Connaughton, Nina Mann, Mohamed A Shalaby, Jameela A Kari, Sherif ElDesoky, Velibor Tasic, Loai A Eid, Shirlee Shril, David M Thal, Friedhelm Hildebrandt
Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA., Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia., Department of Pediatrics, Pediatric Nephrology Unit, Pediatric Nephrology Center of Excellence, Faculty of Medicine, King Abdulaziz University Hospital, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia., Pediatric Nephrology, University Children's Hospital, University of Skopje Medical Faculty, Skopje, North Macedonia., Pediatric Nephrology Department, Dubai Hospital, Dubai, UAE.