Gene expression of muscular and neuronal pathways is cooperatively dysregulated in patients with idiopathic achalasia.

Orazio Palmieri,Angelo Andriulli,Massimo Carella,Tiziana Latiano,Orazio Palumbo,Paolo Graziano,Caterina Fusilli,Giuseppina Martino,Antonello Cuttitta,Fabrizio Bossa,Giuseppe Corritore,Tommaso Mazza,Lucia Anna Muscarella,Anna Latiano,Antonio Merla

doi:10.1038/srep31549

Abstract

Idiopathic achalasia is characterized by the absence of peristalsis secondary to loss of neurons in the myenteric plexus that hampers proper relaxation of the lower esophageal sphincter. Achalasia can be considered a multifactorial disorder as it occurs in related individuals and is associated with HLA class II genes, thereby suggesting genetic influence. We used microarray technology and advanced in-silico functional analyses to perform the first genome-wide expression profiling of mRNA in tissue samples from 12 achalasia and 5 control patients. It revealed 1,728 differentially expressed genes, of these, 837 (48.4%) were up-regulated in cases. In particular, genes participating to the smooth muscle contraction biological function were mostly up-regulated. Functional analysis revealed a significant enrichment of neuronal/muscular and neuronal/immunity processes. Upstream regulatory analysis of 180 genes involved in these processes suggested TLR4 and IL18 as critical key-players. Two functional gene networks were significantly over-represented: one involved in organ morphology, skeletal muscle system development and function, and neurological diseases, and the other participating in cell morphology, humoral immune response and cellular movement. These results highlight on pivotal genes that may play critical roles in neuronal/muscular and neuronal/immunity processes, and that may contribute to the onset and development of achalasia.

Highlights

Idiopathic achalasia is characterized by the absence of peristalsis secondary to loss of neurons in the myenteric plexus that hampers proper relaxation of the lower esophageal sphincter
Idiopathic achalasia is an inflammatory disease of unknown etiology, characterized by the lack of coordinated peristalsis and incomplete relaxation of the lower esophageal sphincter (LES) due to loss of inhibitory nitrinergic neurons in the esophageal myenteric plexus
Idiopathic achalasia is characterized by the destruction of myenteric neurons synthesizing nitric oxide (NO), responsible for the inhibitory component of esophageal peristalsis and LES relaxation

Summary

Introduction

Idiopathic achalasia is characterized by the absence of peristalsis secondary to loss of neurons in the myenteric plexus that hampers proper relaxation of the lower esophageal sphincter. Two functional gene networks were significantly over-represented: one involved in organ morphology, skeletal muscle system development and function, and neurological diseases, and the other participating in cell morphology, humoral immune response and cellular movement These results highlight on pivotal genes that may play critical roles in neuronal/muscular and neuronal/immunity processes, and that may contribute to the onset and development of achalasia. Current evidence suggests that the initial insult to the esophagus, most likely a viral infection or other environmental factor, causes inflammation in the myenteric plexus and leads to an autoimmune response in genetically susceptible individuals, with subsequent chronic destruction of inhibitory myenteric ganglion cells resulting in the clinical syndrome of idiopathic achalasia[3]

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Results

Conclusion