Novel understanding on genetic mechanisms of enteric neuropathies leading to severe gut dysmotility

Abstract

The enteric nervous system (ENS) is the third division of the autonomic autonomic nervous system and the largest collection of neurons outside the central nervous system (CNS). The ENS has been referred to as "the brain in the gut" or "the second brain of the human body" because of its highly integrated neural circuits controlling a vast repertoire of gut functions, including absorption/secretion, splanchnic blood vessels, some immunological aspects, intestinal epithelial barrier, and gastrointestinal (GI) motility. The latter function is the result of the ENS fine-tuning over smooth musculature, along with the contribution of other key cells, such as enteric glia (astrocyte like cells supporting and contributing to neuronal activity), interstitial cells of Cajal (the pacemaker cells of the GI tract involved in neuromuscular transmission), and enteroendocrine cells (releasing bioactive substances, which affect gut physiology). Any noxa insult perturbing the ENS complexity may determine a neuropathy with variable degree of neuro-muscular dysfunction. In this review, we aim to cover the most recent update on genetic mechanisms leading to enteric neuropathies ranging from Hirschsprung's disease (characterized by lack of any enteric neurons in the gut wall) up to more generalized form of dysmotility such as chronic intestinal pseudo-obstruction (CIPO) with a significant reduction of enteric neurons. In this line, we will discuss the role of the RAD21 mutation, which we have demonstrated in a family whose affected members exhibited severe gut dysmotility. Other genes contributing to gut motility abnormalities will also be presented. In conclusion, the knowledge on the molecular mechanisms involved in enteric neuropathy may unveil strategies to better manage patients with neurogenic gut dysmotility and pave the way to targeted therapies.

Figure 1.

Possible topography of some genetic variants involved in gut neuro-muscular impairment and related dysmotility. MYLK, Myosin light chain kinase; MYL9, Myosin light chain 9; ACTG2, Enteric smooth muscle actin γ-2; LMOD1, leiomodin 1; MYH11, Myosin heavy chain 11; FLNA, filamin A; RAD21, Cohesin Complex Component; SGOL1, Shugoshin-like 1; TYMP, Thymidine phosphorylase gene; POLG, DNA polymerase gamma; LIG3, ligase III gene. IPAN, intrinsic primary afferent neuron; ICC, interstitial cells of Cajal; *genes associated to myopathic forms of CIPO. Created with BioRender.

Figure 2.

Mutated LIG3 mitochondrial-related entero-neuropathy. In the cryostat sections, few HuC/D immunolabeled (green) myenteric cell bodies (arrows) were observed in the gut (colon) biopsies of patients with LIG3 causative variants vs controls. Cell nuclei were stained with DAPI (blue). Quantitative analysis (graph below) confirmed that myenteric neurons were significantly reduced in patients carrying the causative variants in LIG3, compared to controls (p≤0.005 control vs patient-1 and p≤0.05 control vs patient-2 and 3; ANOVA). Scale bar: 50 μm. Photomicrographs in D, H, L and P illustrate higher magnification insets of the indicated region. Scale bar: 20 μm.