Abstract: PO1635
CHRM5 Mutations as a Potential Cause of Neurogenic Bladder
Session Information
- Genetic Diseases of the Kidneys: Non-Cystic - 2
October 22, 2020 | Location: On-Demand
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1002 Genetic Diseases of the Kidneys: Non-Cystic
Authors
- Schneider, Sophia, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA, Boston, Massachusetts, United States
- Schierbaum, Luca M., Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA, Boston, Massachusetts, United States
- Seltzsam, Steve, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA, Boston, Massachusetts, United States
- Wang, Chunyan, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA, Boston, Massachusetts, United States
- Zheng, Bixia, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA, Boston, Massachusetts, United States
- Wu, Chen-Han Wilfred, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA, Boston, Massachusetts, United States
- Nakayama, Makiko, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA, Boston, Massachusetts, United States
- Shril, Shirlee, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA, Boston, Massachusetts, United States
- Hildebrandt, Friedhelm, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA, Boston, Massachusetts, United States
Background
Neurogenic bladder is caused by disruption of neuronal pathways that regulate bladder relaxation and contraction. In severe cases, neurogenic bladder can lead to vesicoureteral reflux, recurrent urinary tract infections, and even chronic kidney disease and renal failure. These symptoms overlap with the manifestations of congenital anomalies of the kidneys and urinary tract (CAKUT). Animal models of bladder dysfunction suggest that neurogenic bladder can be caused by single gene mutations (PNAS 96:5746, 1999).
Methods
To identify novel monogenic causes of neurogenic bladder we applied whole exome sequencing (WES) to our worldwide cohort of families with CAKUT.
Results
By WES, we discovered a homozygous missense variant (p.Gln184Arg) in the gene CHRM5 (cholinergic receptor, muscarinic, 5) in a patient from a non-consanguineous family with CKD stage 4 secondary to neurogenic bladder with small trabeculated bladder, severe right-sided vesicoureteral reflux (VUR) and bilateral hydronephrosis. Evaluation of WES data of 703 additional patients with CAKUT did not identify further families with mutations in CHRM5. CHRM5 codes for a seven transmembrane-spanning G-protein coupled muscarinic acetylcholine receptor. Crystal structure modeling shows the mutation p.Gln184Arg affecting the second extra-cellular loop between the transmembrane spanning alpha helices 4 and 5. The receptor CHRM5 is shown to be expressed in murine and human bladder wall.
We propose CHRM5 to be involved in bladder tone regulation and that the molecular defect of our patient causes neurogenic bladder with secondary symptoms as CAKUT. This is similar to CHRNA3, which we published as the first gene to cause neurogenic bladder (AJHG 105:186, 2019). Deckmann et al (FASIB J. 32:2903, 2018) demonstrate that Chrm5 knockout mice show symptoms of bladder overactivity. Functional studies testing the effect of the variant p.Gln184Arg on CHRM5’s receptor function are pending.
Conclusion
We identified a recessive mutation in CHRM5 as a potential cause of neurogenic bladder in humans.
Funding
- Other NIH Support