Alternative titles; symbols
Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
---|---|---|---|---|---|---|
15q25.1 | Bladder dysfunction, autonomic, with impaired pupillary reflex and secondary CAKUT | 191800 | Autosomal recessive | 3 | CHRNA3 | 118503 |
A number sign (#) is used with this entry because of evidence that autonomic bladder dysfunction with impaired pupillary reflex and secondary congenital anomalies of the kidney and urinary tract (BAIPRCK) is caused by homozygous mutation in the CHRNA3 (118503) gene on chromosome 15q25.
Autonomic bladder dysfunction with impaired pupillary reflex and secondary CAKUT (congenital anomalies of the kidney and urinary tract) is an autosomal recessive neurogenic disorder with onset in utero or early childhood. Affected individuals have impaired neuronal bladder and ureteral innervation causing coordination defects that result in secondary structural defects of the renal system, including hydronephrosis, vesicoureteral reflux (VUR), and small kidneys, that may result in chronic kidney disease as well as recurrent urinary tract infections (UTIs). Surgical treatment of VUR is not effective. Most individuals also have additional autonomic features, most commonly impaired pupillary reflex and sometimes orthostatic hypotension (summary by Mann et al., 2019).
Mann et al. (2019) reported 5 patients from 3 unrelated families, 2 of which were consanguineous, with autonomic dysfunction of the bladder and ureters. The first family, of Arab origin, had 2 affected brothers. One was a 19-year-old man who had recurrent urinary tract infections (UTIs) since childhood, vesicoureteral reflux, hydronephrosis, a thick bladder wall, post-void residual content, and a small atrophic left kidney with 10% residual function. He also had impaired pupillary light reflex and orthostatic hypotension, consistent with autonomic involvement. His affected brother had recurrent UTIs with normal renal and bladder ultrasound, as well as an impaired pupillary light reflex. Two sibs of Pakistani descent presented in utero with hydronephrosis and hydroureteronephrosis. The boy, who had a right cystic kidney and hypospadias, underwent vesicostomy. His sister had recurrent UTIs and voiding dysfunction. These sibs had constant miosis with pupils that did not dilate, as well as flat fetal heart tracings in utero resulting in emergency C-section in 1 at 36 weeks' gestation. The boy had additional unrelated features, including dysmorphic facies and impaired intellectual development, likely associated with a de novo heterozygous duplication at chromosome 2q31.1-q32.3 (see 613681). The last patient was a Macedonian girl with early-onset VUR that recurred after surgery. She was not noted to have autonomic features, but she was ascertained from a cohort of 380 with CAKUT who underwent whole-exome sequencing.
The transmission pattern of BAIPRCK in the families reported by Mann et al. (2019) was consistent with autosomal recessive inheritance.
In 5 patients from 3 unrelated families with BAIPRCK, Mann et al. (2019) identified homozygous loss-of-function mutations in the CHRNA3 gene (118503.0002-118503.0004). The mutations, which were found by exome sequencing and homozygosity mapping (in 2 families) and confirmed by Sanger sequencing, were either not present in the gnomAD database or were present at a low frequency only in the heterozygous state. In vitro functional electrophysiologic and immunofluorescence studies in HEK293 cells showed that all the mutations resulted in abolition of the AChR channel current in response to ACh, consistent with a complete loss of function. Moreover, the truncating and frameshift mutations additionally resulted in impaired expression of the mutated protein at the plasma membrane compared to controls, indicating a further loss-of-function effect.
The alpha-3 subunit of the neuronal nicotinic acetylcholine receptor is widely expressed in autonomic ganglia and in some parts of the brain. The alpha-3 subunit can form heteromultimeric ion channels with other alpha subunits and with beta-2 and beta-4 subunits. To understand better the function of CHRNA3 in vivo, Xu et al. (1999) prepared a null mutation for the alpha-3 gene by the deletion of exon 5 and found that homozygous -/- mice lacked detectable mRNA on Northern blotting. The null mice survived to birth but had impaired growth and increased mortality before and after weaning. The null mice had extreme bladder enlargement, dribbling urination, bladder infection, urinary stones, and widely dilated ocular pupils that did not contract in response to light. Detailed histologic studies of null mice showed no significant abnormalities in brain or peripheral tissues except urinary bladder, where inflammation was prominent. Ganglion cells and axons were present in bladder and bowel. Bladder strips from null mice failed to contract in response to 0.1 mM nicotine, but did contract in response to electrical field stimulation or carbamoylcholine. The number of acetylcholine-activated single-channel currents was severely reduced in the neurons of superior cervical ganglia in null mice with 5 physiologically distinguishable nicotinic acetylcholine receptor subtypes with different conductance and kinetic properties in wildtype mice, all of which were reduced in null mice. The findings in the alpha-3-null mice suggested that this subunit is an essential component of the nicotinic receptors mediating normal function of the autonomic nervous system.
Gundrum (1922) described a family in which 9 individuals (8 male, 1 female) spanning 3 generations had bladder atony. The transmission pattern was consistent with autosomal dominant inheritance. Most performed catheterization daily on themselves.
Gundrum, F. F. Familial bladder atony. JAMA 78: 411-412, 1922.
Mann, N., Kause, F., Henze, E. K., Gharpure, A., Shril, S., Connaughton, D. M., Nakayama, M., Klambt, V., Majmundar, A. J., Wu, C.-H. W., Kolvenbach, C. M., Dai, R., and 21 others. CAKUT and autonomic dysfunction caused by acetylcholine receptor mutations. Am. J. Hum. Genet. 105: 1286-1293, 2019. [PubMed: 31708116] [Full Text: https://doi.org/10.1016/j.ajhg.2019.10.004]
Xu, W., Gelber, S., Orr-Urtreger, A., Armstrong, D., Lewis, R. A., Ou, C.-N., Patrick, J., Role, L., De Biasi, M., Beaudet, A. L. Megacystis, mydriasis, and ion channel defect in mice lacking the alpha-3 neuronal nicotinic acetylcholine receptor. Proc. Nat. Acad. Sci. 96: 5746-5751, 1999. [PubMed: 10318955] [Full Text: https://doi.org/10.1073/pnas.96.10.5746]