Muscarinic Acetylcholine Receptor M3 Mutation Causes Urinary Bladder Disease and a Prune-Belly-like Syndrome

Weber, Stefanie; Thiele, Holger; Mır, Sevgı; Toliat, Mohammad Reza; Sozeri, Betul; Reutter, Heiko; Draaken, Markus; Ludwig, Michael; Altmüller, Janine; Frommolt, Peter; Stuart, Helen M.; Ranjzad, Parisa; Hanley, Neil A.; Jennings, Rachel; Newman, William G.; Wilcox, Duncan T.; Thiel, Uwe; Schlingmann, Karl Peter; Beetz, Rolf; Hoyer, Peter F.; Konrad, Martin; Schaefer, Franz; Nürnberg, Peter; Woolf, Adrian S.

doi:10.1016/j.ajhg.2011.10.007

Cited by 94 publications

(80 citation statements)

References 29 publications

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“…Affected individuals were found to harbor recessive mutations in CHRM3 (muscarinic acetylcholine receptor M3) (Table 15.3 ) [ 60 ]. A knock out mouse model for CHRM3 exhibits a similar phenotype.…”

Section: Hpse2 Lrig2 and Chrm3-monogenic Causes Of Urinary Bladder mentioning

confidence: 99%

Genetics of Congenital Anomalies of the Kidneys and Urinary Tract

Vivante

Hildebrandt

2016

Congenital Anomalies of the Kidney and Urinary Tract

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Section: Hpse2 Lrig2 and Chrm3-monogenic Causes Of Urinary Bladder mentioning

confidence: 99%

Genetics of Congenital Anomalies of the Kidneys and Urinary Tract

Vivante

Hildebrandt

2016

Congenital Anomalies of the Kidney and Urinary Tract

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“…Recently, the NNCS was shown not to be regulated on the mRNA level in this disease [143] whereas a downregulation was measured for the neuronal nAChR subunits α 10 and α 5 (dorsal root ganglia L5-S2) [144]. Further, a mutation of the M3 mAChR is associated with the onset of bladder outlet obstruction [145]. However, the plasticity at the level of innervation leads to the assumption that the autonomic nervous system is most involved in bladder outlet obstruction, eventually in interaction with the NNCS [142].…”

Section: Urinary Systemmentioning

confidence: 99%

The Non-Neuronal Cholinergic System in Health and Disease

Beckmann¹,

Lips²

2013

Pharmacology

102

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Acetylcholine (ACh) is not only a neurotransmitter but is an ancient molecule that can be released by and act on non-neuronal cells. In these cells the system of ACh-synthesizing enzymes, transporters, receptors and degrading enzymes is termed the non-neuronal cholinergic system (NNCS). There is increasing evidence that the NNCS is dysregulated in various diseases and can have an influence on their pathology. However, for many organ systems not much is known about the expression and function of the NNCS. Thus, this review focusses on the role of the NNCS in different organ systems in health and disease. Dysregulation of ACh synthesis and release, mutations or polymorphisms in genes encoding NNCS components, and auto-antibodies against NNCS components are common factors influencing disease progression. Pharmacological agents targeting the NNCS are already successfully in clinical use for some disorders, indicating that interfering with this system is very promising and more research is needed to elucidate the role of the NNCS in different tissues and pathological states.

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“…Here, there is an analogy with another congenital bladder disease in which M3, the cholinergic receptor mediating detrusor contraction, is mutated. 25 Mating heterozygous mice carrying a gene trap in intron 6 of Hpse2 led to birth of wild-type, heterozygous, and homozygous offspring in Mendelian ratios. Homozygous mutant tissue contained a truncated Hpse2 transcript but lacked wild-type Hpse2 transcripts extending beyond the trap ( Figure 3A).…”

mentioning

confidence: 99%

Urinary Tract Effects of HPSE2 Mutations

Stuart

Roberts

Hilton

et al. 2015

Journal of the American Society of Nephrology

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Urofacial syndrome (UFS) is an autosomal recessive congenital disease featuring grimacing and incomplete bladder emptying. Mutations of HPSE2, encoding heparanase 2, a heparanase 1 inhibitor, occur in UFS, but knowledge about the HPSE2 mutation spectrum is limited. Here, seven UFS kindreds with HPSE2 mutations are presented, including one with deleted asparagine 254, suggesting a role for this amino acid, which is conserved in vertebrate orthologs. HPSE2 mutations were absent in 23 nonneurogenic neurogenic bladder probands and, of 439 families with nonsyndromic vesicoureteric reflux, only one carried a putative pathogenic HPSE2 variant. Homozygous Hpse2 mutant mouse bladders contained urine more often than did wild-type organs, phenocopying human UFS. Pelvic ganglia neural cell bodies contained heparanase 1, heparanase 2, and leucine-rich repeats and immunoglobulin-like domains-2 (LRIG2), which is mutated in certain UFS families. In conclusion, heparanase 2 is an autonomic neural protein implicated in bladder emptying, but HPSE2 variants are uncommon in urinary diseases resembling UFS.

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Muscarinic Acetylcholine Receptor M3 Mutation Causes Urinary Bladder Disease and a Prune-Belly-like Syndrome

Cited by 94 publications

References 29 publications

Genetics of Congenital Anomalies of the Kidneys and Urinary Tract

Genetics of Congenital Anomalies of the Kidneys and Urinary Tract

The Non-Neuronal Cholinergic System in Health and Disease

Urinary Tract Effects of HPSE2 Mutations

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