https://doi.org/10.4081/ejh.2021.3289
Novel understanding on genetic mechanisms of enteric neuropathies leading to severe gut dysmotility
Submitted: 14 June 2021
Accepted: 3 November 2021
Published: 25 November 2021
Accepted: 3 November 2021
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All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
Authors
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.
Holland AM, Bon-Frauches AC, Keszthelyi D, Melotte V, Boesmans W. The enteric nervous system in gastrointestinal disease etiology. Cell Mol Life Sci 2021;78:4713-33.
DOI: https://doi.org/10.1007/s00018-021-03812-y
Nick J Spencer, Hongzhen Hu. Enteric nervous system: sensory transduction, neural circuits and gastrointestinal motility. Nat Rev Gastroenterol Hepatol 2020;17:338-51.
DOI: https://doi.org/10.1038/s41575-020-0271-2
Langley JN. On the reaction of cells and of nerve-endings to certain poisons, chiefly as regards the reaction of striated muscle to nicotine and to curare. J Physiol 1905;33:374-413.
DOI: https://doi.org/10.1113/jphysiol.1905.sp001128
Furness J.B. The enteric nervous system and neurogastroenterology. Nat Rev Gastroenterol Hepatol 2012;9:286-94.
DOI: https://doi.org/10.1038/nrgastro.2012.32
Sternini C, Wong H, Pham T, De Giorgio R, Miller LJ, Kuntz SM, et al. Expression of cholecystokinin a receptors in neurons innervating the rat stomach and intestine. Gastroenterology 1999;117:1136-46.
DOI: https://doi.org/10.1016/S0016-5085(99)70399-9
De Giorgio R, Barbara G, Furness JB, Tonini M. Novel therapeutic targets for enteric nervous system disorders. Trends Pharmacol Sci 2007;28:473-81.
DOI: https://doi.org/10.1016/j.tips.2007.08.003
Berger M, Gray AJ, Roth BL. The expanded biology of serotonin. Annu Rev Med 2009;60:355-66.
DOI: https://doi.org/10.1146/annurev.med.60.042307.110802
Ochoa-Cortes F, Turco F, Linan-Rico A, Soghomonyan S, Whitaker E, Wehner S, et al. Enteric glial cells: A new frontier in neurogastroenterology and clinical target for inflammatory bowel diseases. Inflamm Bowel Dis 2016;22:433-49.
DOI: https://doi.org/10.1097/MIB.0000000000000667
Gulbransen BD, Sharkey KA. Novel functional roles for enteric glia in the gastrointestinal tract. Nat Rev Gastroenterol Hepatol 2012;9:625-32.
DOI: https://doi.org/10.1038/nrgastro.2012.138
Neunlist M, Rolli-Derkinderen M, Latorre R, Van Landeghem L, Coron E, Derkinderen P, et al. Enteric glial cells: recent developments and future directions. Gastroenterology 2014;147:1230-7.
DOI: https://doi.org/10.1053/j.gastro.2014.09.040
Boschetti E, Malagelada C, Accarino A, Malagelada JR, Cogliandro RF, Gori A, et al. Enteric neuron density correlates with clinical features of severe gut dysmotility. Am J Physiol Gastrointest Liver Physiol 2019;317:G793-G801.
DOI: https://doi.org/10.1152/ajpgi.00199.2019
Knowles CH, Lindberg G, Panza E, De Giorgio R. New perspectives in the diagnosis and management of enteric neuropathies. Nat Rev Gastroenterol Hepatol 2013;10:206-18.
DOI: https://doi.org/10.1038/nrgastro.2013.18
Pawolski V, Schmidt HHM. Neuron-glia interaction in the developing and adult enteric nervous system. Cells 2021;10:47.
DOI: https://doi.org/10.3390/cells10010047
Brooks AS, Oostra BA, Hofstra RM. Studying the genetics of Hirschsprung’s disease: unraveling an oligogenic disorder. Clin Genet 2005;67 6-14.
DOI: https://doi.org/10.1111/j.1399-0004.2004.00319.x
Luzón-Toro B, Villalba-Benito L, Torroglosa A, Fernández MR, Antiñolo G, Borrego S. What is new about the genetic background of Hirschsprung disease? Clin Genet 2020;97:114-24.
DOI: https://doi.org/10.1111/cge.13615
Zhang Z, Li Q, Diao M, Liu N, Cheng W, Xiao P, Zou J, et al. Sporadic Hirschsprung disease: mutational spectrum and novel candidate genes revealed by nextgeneration sequencing. Sci Rep. 2017;7:14796.
DOI: https://doi.org/10.1038/s41598-017-14835-6
De Giorgio R, Cogliandro RF, Barbara G, Corinaldesi R, Stanghellini V. Chronic intestinal pseudo-obstruction: clinical features, diagnosis, and therapy. Gastroenterol Clin North Am 2011;40:787-807.
DOI: https://doi.org/10.1016/j.gtc.2011.09.005
De Giorgio R, Sarnelli G, Corinaldesi R, Stanghellini V. Advances in our understanding of the pathology of chronic intestinal pseudo-obstruction. Gut 2004;53:1549-52.
DOI: https://doi.org/10.1136/gut.2004.043968
Joly F, Amiot A, Messing B. Nutritional support in the severely compromised motility patient: when and how? Gastroenterol Clin North Am 2011;40:845-51.
DOI: https://doi.org/10.1016/j.gtc.2011.09.010
Di Nardo G, Di Lorenzo C, Lauro A, Stanghellini V, Thapar N, Karunaratne TB, et al. Chronic intestinal pseudo-obstruction in children and adults: diagnosis and therapeutic options. Neurogastroenterol Motil 2017;29:e12945.
DOI: https://doi.org/10.1111/nmo.12945
Halim D, Wilson MP, Oliver D, Brosens E, Verheij JBGM, Han Y, et al. Loss of LMOD1 impairs smooth muscle cytocontractility and causes megacystis microcolon intestinal hypoperistalsis syndrome in humans and mice. Proc Natl Acad Sci USA 2017;114:E2739-47.
DOI: https://doi.org/10.1073/pnas.1620507114
Moreno CA, Metze K, Lomazi EA, Bertola DR, Almeida Barbosa RH, Cosentino V, et al. Visceral myopathy: Clinical and molecular survey of a cohort of seven new patients and state of the art of overlapping phenotypes. Am J Med Genet A 2016;170:2965-74.
DOI: https://doi.org/10.1002/ajmg.a.37857
Batzir NA, Bhagwat PK, Larson A, Akdemir ZC, Bagłaj M, Bofferding L, et al. Recurrent arginine substitutions in the ACTG2 gene are the primary driver of disease burden and severity in visceral myopathy. Hum Mutat 2020;41:641-54.
DOI: https://doi.org/10.1002/humu.23960
Matera I, Bordo D, Di Duca M, Lerone M, Santamaria G, Pongiglione M, et al. Novel ACTG2 variants disclose allelic heterogeneity and bi-allelic inheritance in pediatric chronic intestinal pseudo-obstruction. Clin Genet 2021;99:430-6.
DOI: https://doi.org/10.1111/cge.13895
Chetaille P, Preuss C, Burkhard S, Côté JM, Houde C, Castilloux J, et al. Mutations in SGOL1 cause a novel cohesinopathy affecting heart and gut rhythm. Nat Genet 2014;46:1245-9.
DOI: https://doi.org/10.1038/ng.3113
Bonora E, Bianco F, Cordeddu L, Bamshad M, Francescatto L, Dowless D, et al. Mutations in RAD21 disrupt regulation of APOB in patients with chronic intestinal pseudo-obstruction. Gastroenterology 2015;148:771-82.
DOI: https://doi.org/10.1053/j.gastro.2014.12.034
Horsfield JA, Print CG, Mönnich M. Diverse developmental disorders from the one ring: Distinct molecular pathways underlie the cohesinopathies. Front Genet 2012;3:171.
DOI: https://doi.org/10.3389/fgene.2012.00171
Bianco F, Eisenman ST, Colmenares Aguilar MG, Bonora E, Clavenzani P, Linden DR, et al. Expression of RAD21 immunoreactivity in myenteric neurons of the human and mouse small intestine. Neurogastroenterol Motil 2018;30:e13429.
DOI: https://doi.org/10.1111/nmo.13429
Filosto M, Cotti Piccinelli S, Caria F, Gallo Cassarino S, Baldelli E, Galvagni A, et al. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE-MTDPS1). J Clin Med 2018;7:389.
DOI: https://doi.org/10.3390/jcm7110389
Giordano C, Sebastiani M, De Giorgio R, Travaglini C, Tancredi A, Valentino ML et al. Gastrointestinal dysmotility in mitochondrial neurogastrointestinal encephalomyopathy is caused by mitochondrial DNA depletion. Am J Pathol 2008;173:1120-8.
DOI: https://doi.org/10.2353/ajpath.2008.080252
Boschetti E, D’Alessandro R, Bianco F, Carelli V, Cenacchi G, Pinna AD et al. Liver as a Source for thymidine phosphorylase replacement in mitochondrial neurogastrointestinal encephalomyopathy. Plos One 2014;9:e96692.
DOI: https://doi.org/10.1371/journal.pone.0096692
Martí R, López LC, Hirano M. Assessment of thymidine phosphorylase function: measurement of plasma thymidine (and deoxyuridine) and thymidine phosphorylase activity. Methods Mol Biol 2012;837:121-33.
DOI: https://doi.org/10.1007/978-1-61779-504-6_8
Bonora E, Chakrabarty S, Kellaris G, Tsutsumi M, Bianco F, Bergamini C, et al. Biallelic variants in LIG3 cause a novel mitochondrial neurogastrointestinal encephalomyopathy. Brain 2021;144:1451-66.
DOI: https://doi.org/10.1093/brain/awab056
Lehmann R, Lee CM, Shugart EC, Benedetti M, Charo RA, Gartner Z, et al. Human organoids: a new dimension in cell biology. Mol Biol Cell 2019;30:1129-37.
DOI: https://doi.org/10.1091/mbc.E19-03-0135
Workman MJ, Mahe MM, Trisno S, Poling PH, Watson CL, Sundaram N, et al. Engineered human pluripotent-stem-cell-derived intestinal tissues with a functional enteric nervous system. Nat Med 2017;23:49-59.
DOI: https://doi.org/10.1038/nm.4233
Morarach K, Mikhailova A, Knoflach V, Memic F, Kumar R, Li W, et al. Diversification of molecularly defined myenteric neuron classes revealed by single cell RNA-sequencing. Nat Neurosci 2021;24:34-46.
DOI: https://doi.org/10.1038/s41593-020-00736-x
Ganz J, Melancon E, Wilson C, Amores A, Batzel P, Strader M, et al. Epigenetic factors Dnmt1 and Uhrf1 coordinate intestinal development. Dev Biol 2019;455:473-84.
DOI: https://doi.org/10.1016/j.ydbio.2019.08.002
May-Zhang AA, Tycksen E, Southard-Smith NA, Deal KK, Benthal JT, Buehler DP, et al. Combinatorial transcriptional profiling of mouse and human enteric neurons identifies shared and disparate subtypes in situ. Gastroenterology 2021;160:755-70.
DOI: https://doi.org/10.1053/j.gastro.2020.09.032
How to Cite
Bianco, F. ., Lattanzio, G., Lorenzini, L. ., Diquigiovanni, C., Mazzoni, M. ., Clavenzani, P., … De Giorgio, R. (2021). Novel understanding on genetic mechanisms of enteric neuropathies leading to severe gut dysmotility. European Journal of Histochemistry, 65(s1). https://doi.org/10.4081/ejh.2021.3289
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