Characterization of the human β4 nAChR gene and polymorphisms in CHRNA3 and CHRNB4

Abstract

Most neuronal nicotinic acetylcholine receptors are heteropentamers, composed of α and subunits. Mice lacking the α3 subunit and mice lacking both the 2 and 4 subunits, but not mice lacking the 2 or 4 subunits alone, have a severe phenotype characterized by megacystis, failure of bladder strips to contract in response to nicotine, widely dilated ocular pupils, growth failure, and perinatal mortality. The deficit in bladder contraction was also found in mice lacking only the 4 subunit, although they did not develop megacystis. The major bladder phenotype resembles the human autosomal recessive disorder of megacystis-microcolon-hypoperistalsis syndrome (MMIHS). Based on the similarity of the mouse and human phenotypes, we initiated mutation analyses in the α3 and 4 genes in MMIHS families. The human gene encoding the 4 subunit was fully characterized, including refinement of its mapping. Analysis of disease families and controls identified numerous genetic variants, including high-frequency polymorphisms in both CHRNA3 and CHRNB4. Although no loss-of-function mutations have been identified to date, these genes remain strong candidates for involvement in MMIHS, because various mutations might be obscured within the complex cluster of genes. Some of the markers presented here are valuable tools for analysis of the role of genetic variation in responses to nicotine and for characterization of various dysautonomic abnormalities.

Prenatal Diagnosis of Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome in One Fetus of a Twin Pregnancy

“…Although the genetic basis of the syndrome is not firmly established, there are reports for mutations and polymorphisms in the alpha3 subunit containing nicotinic acetylcholine (nAchR) and beta4 nAchR genes responsible for the expression of neuronal acetylcholine receptors in family and patients with MMIHS. 7 The persistently enlarged stomach we observed in our patient prenatally is rarely reported. 8 Nueropathyy or myopathy may result in an impairment of stomach contraction.…”

Heterozygous De Novo and Inherited Mutations in the Smooth Muscle Actin (ACTG2) Gene Underlie Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome

“…We collected samples from patients with MMIHS and related phenotypes, some of whom have been previously reported [31]. Our cohort of 34 families to date includes 27 DNA samples from probands including individuals diagnosed with MMIHS (20 probands) as well as intestinal pseudo-obstruction (4 probands), prune belly syndrome (2 probands), and hollow visceral myopathy (1 proband).…”

“…A role for the α3 subunit was further suggested when reduced mRNA levels were measured by in situ hybridization, and reduced immunostaining for protein was possibly found in tissues from MMIHS patients [29]. However, antibodies against the neuronal nicotinic receptor subunits are notoriously unreliable [30] and a specific search for mutations in CHRNA3 and CHRNB4 in many of the patients studied herein did not identify any potential disease-causing mutations [31].…”

Recurrent arginine substitutions in the ACTG2 gene are the primary driver of disease burden and severity in visceral myopathy

“…Evidence from mouse models indicated that impairment of cholinergic neurotransmission, which initiates the process leading to smooth muscle contraction, results in dilated bladder, and mydriasis (Lev-Lehman, Bercovich, Xu, Stockton, & Beaudet, 2001).…”