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Abstract: FR-OR077

CHRNA3 Mutations Cause Neurogenic Bladder and Dysautonomia

Session Information

Category: Genetic Diseases of the Kidney

  • 1002 Genetic Diseases of the Kidney: Non-Cystic


  • Kause, Franziska, Boston Children''s Hospital, Boston, Massachusetts, United States
  • Mann, Nina, Boston Children's Hospital, Boston, Massachusetts, United States
  • Shril, Shirlee, Boston Childrens Hospital, Boston, Massachusetts, United States
  • Connaughton, Dervla M., Boston Children's Hospital, Boston, Massachusetts, United States
  • Kolvenbach, Caroline M., Harvard Medical School, Boston, Massachusetts, United States
  • Dai, Rufeng, Boston Children's Hospital, Boston, Massachusetts, United States
  • Nakayama, Makiko, Boston Children's Hospital, Boston, Massachusetts, United States
  • De Franco, Elisa, Royal Devon and Exeter NHS Foundation Trust, Exeter, United Kingdom
  • Ellard, Sian, University of Exeter Medical School, Exeter, United Kingdom
  • Tasic, Velibor, University Children's Hospital, Skopje, Macedonia (the former Yugoslav Republic of)
  • Beckel, Jonathan M., University of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • Hildebrandt, Friedhelm, Boston Children's Hospital, Boston, Massachusetts, United States

Group or Team Name

  • Boston Children's Hospital, Division of Nephrology

Congenital anomalies of the kidneys and urinary tract (CAKUT) are the most prominent cause (>45%) of chronic kidney disease (CKD) in the first 3 decades of life. Although about 40 monogenic causes have been implicated in human CAKUT so far, many causes remain unknown.


To identify novel monogenic causes of CAKUT we applied whole exome sequencing (WES) to 144 families with CAKUT.


By WES, we discovered a homozygous frameshift mutation (p.Thr337Asnfs*81) in the gene CHRNA3 (cholinergic receptor nicotinic alpha 3 subunit) in a patient of consanguineous descent with CKD stage 3 secondary to neurogenic bladder, vesicoureteral reflux (VUR) and bilateral hydronephrosis. Screening WES data of 703 further patients with CAKUT revealed three different homozygous recessive CHRNA3 mutations in 3 families with neurogenic bladder (p.Ser340*; c.267+2T>G obligatory splice site mutation; p.Arg110His).
CHRNA3 codes for an ion channel subunit in the urothelium and interacts with other ion channels in the neuronal network governing bladder reflexes and smooth muscle contraction. A Chrna3 knockout mouse has impaired bladder reflexes, a distended urinary bladder, dribbling urination, urinary tract infections, urinary stones and mydriasis (Xu PNAS 96:5746, 1999). Given the mydriasis in mice we inquired for constant mydriasis in the patients. This was confirmed for the index patient with p.Thr337Asnfs*81 and two affected siblings with the p.Ser340* mutation.


We identified CHRNA3 recessive mutations as the first cause of neurogenic bladder in humans. The mutations caused additionally extrarenal dysautonomic phenotypes such as constant mydriasis. Our findings may disclose a pathophysiological sequence, in which neurogenic bladder secondarily causes CAKUT.