Kidney Week

Abstract: FR-OR077

CHRNA3 Mutations Cause Neurogenic Bladder and Dysautonomia

Session Information

• Genetics and Kidney Diseases: Beyond PKD
  October 26, 2018 | Location: 33C, San Diego Convention Center
  Abstract Time: 06:18 PM - 06:30 PM

Category: Genetic Diseases of the Kidney

• 1002 Genetic Diseases of the Kidney: Non-Cystic

Authors

• Kause, Franziska, Boston Children''s Hospital, Boston, Massachusetts, United States

Franziska Kause

• Mann, Nina, Boston Children's Hospital, Boston, Massachusetts, United States

Nina Mann,

• Shril, Shirlee, Boston Childrens Hospital, Boston, Massachusetts, United States

Shirlee Shril,

• Connaughton, Dervla M., Boston Children's Hospital, Boston, Massachusetts, United States

Dervla M. Connaughton,

• Kolvenbach, Caroline M., Harvard Medical School, Boston, Massachusetts, United States

Caroline M. Kolvenbach,

• Dai, Rufeng, Boston Children's Hospital, Boston, Massachusetts, United States

Rufeng Dai,

• Nakayama, Makiko, Boston Children's Hospital, Boston, Massachusetts, United States

Makiko Nakayama,

• De Franco, Elisa, Royal Devon and Exeter NHS Foundation Trust, Exeter, United Kingdom

Elisa De Franco,

• Ellard, Sian, University of Exeter Medical School, Exeter, United Kingdom

Sian Ellard,

• Tasic, Velibor, University Children's Hospital, Skopje, Macedonia (the former Yugoslav Republic of)

Velibor Tasic,

• Beckel, Jonathan M., University of Pittsburgh, Pittsburgh, Pennsylvania, United States

Jonathan M. Beckel,

• Hildebrandt, Friedhelm, Boston Children's Hospital, Boston, Massachusetts, United States

Friedhelm Hildebrandt,

Group or Team Name

• Boston Children's Hospital, Division of Nephrology

Background

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.

Methods

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

Results

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.

Conclusion

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.