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FUNCTIONAL VERIFICATION AND MECHANISM OF FAM129C GENE MUTATION IN ACHALASIA

Xiaoqing Li 1, Zhi-Qiang Liu 1, Weifeng Chen 1, Pinghong Zhou 1, Quan-Lin Li 1

Affiliations

1 Zhongshan Hospital, Shanghai, China

Summary

AI Generated

Researchers identified FAM129C as a new genetic mutation in esophageal achalasia and demonstrated that Fam129c mutant mice develop achalasia through a B-cell-dependent autoimmune pathway involving GABA-AR autoantibodies.

FAM129C was identified as a new genetic mutation locus through whole-exome sequencing of 22 Trios core families with achalasia in the Han population
Fam129c mutant mice constructed by CRISPR/Cas9 technology exhibited EA phenotype with anatomical features, pathological changes in the esophageal intermuscular plexus, and diastolic dysfunction consistent with EA patients
FAM129C was localized in B cells, and abnormal activation of plasma cells with increased immunoglobulin secretion was observed in mutant mice
Anti-inhibitory neuron autoantibody GABA-AR was elevated in serum and tissue of mutant mice, and specific deletion of B cells or IvIgG treatment partially alleviated the achalasia phenotype
The pathogenic mechanism involves a B-cell-dependent pathway where increased autoantibody secretion causes specific injury to esophageal inhibitory intermuscular neurons leading to neuromuscular dysfunction

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This summary was generated by an AI large language model based on the content transcript. It is for informational purposes only and should not be considered a substitute for clinical judgment. Always rely on your professional expertise and the full clinical context when making clinical decisions.

Abstract

Introduction

Esophageal achalasia (EA) is a rare functional disorder caused by neuromuscular dysfunction at the esophagogastric junction, characterized by impaired diastole of the lower esophageal sphincter (LES) and loss of distal esophageal peristaltic function. The etiology of the disease is still unknown, and the current etiological hypothesis is that the loss of esophageal neurons due to ganglion inflammation caused by an abnormal immune response to infection in a genetically susceptible background affects the function of the muscles innervated by it. Previous studies have suggested that genetic susceptibility may be strongly associated with the onset of achalasia. Based on this platform, our group is one of the largest EA clinical centers in China, and we used whole-exome sequencing and technology validation to screen out a new genetic mutation locus FAM129C from 22 Trios core families with achalasia. This paper intends to investigate whether Fam129c mutant mice have an EA phenotype, and to investigate the pathogenic mechanism of this mutation with multi-omics. This study will provide a new basis for uncovering the genetic cause of EA, a new mouse model for basic EA research, and potential therapeutic targets for the treatment of EA.

Aims & Methods

The new pathogenic genes inherited from the family line of achalasia in the Han population were screened, and the mutant mice were constructed by CRSPR/Cas9 technology. To verify whether the mutant mice have the cardia apopause phenotype, and to explore the specific mechanism of disease in mutant mice through multi-omics joint analysis and in vivo and in vivo validation experiments.

Results

Fam129c mutant mice were successfully constructed, and it was confirmed that they had EA phenotype from anatomical to functional levels. Immunofluorescence results showed that FAM129C was localized in B cells. Abnormal activation of plasma cells in mutant mice, specific deletion of B cells can partially alleviate the achalasia phenotype of mutant mice. Transcriptome sequencing and single-cell sequencing results revealed a significant enrichment of B cell subsets, and differential genes elevated in mutant mice mainly included immunoglobulins. Single-cell BCR repertoire sequencing analysis showed that mutant mice had increased V-J pairing, increased clone number and clone types, and increased immunoglobulin secretion. Further analysis of proteomics results found that the anti-inhibitory neuron autoantibody GABA-AR was elevated in serum and in situ tissue of mutant mice, and the results of ELISA verification in mice were consistent with it. IvIgG treatment of mutant mice in vitro and in vivo can partially alleviate the EA phenotype.

Conclusion

A new potential mutated genes FAM129C in achalasia were identified, and Fam129c mutant mice conforming to the population mutation pattern were established. Fam129c mutant mice have an EA phenotype, and their anatomical features, pathological changes in the esophageal intermuscular plexus and diastolic function of the lower esophagus are consistent with EA patients. Fam129c mutant mice are pathogenic through a B-cell-dependent pathway. Abnormal activation of plasma cells in mutant mice, increased secretion of immunoglobulins, especially anti-neuronal autoantibody GABA-AR, and neuromuscular dysfunction after specific injury of esophageal inhibitory intermuscular neurons, eventually leading to the onset of achalasia.

Conference

UEG Week Copenhagen 2023

Topics

Oesophagus

Submission format

Abstract

Session

PP 01 Oesophageal, gastric and duodenal disorders (Posters)

Citation

United European Gastroenterology Journal 2023; 11 (Supplement 8)

Published

2023

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TISSUE FOLDS ORGANISE COLON LYMPHATICS TO CHANNEL INTERSTITIAL OUTFLOW AND PROMOTE RESILIENCE AGAINST INFLAMMATORY SWELLING

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TISSUE FOLDS ORGANISE COLON LYMPHATICS TO CHANNEL INTERSTITIAL OUTFLOW AND PROMOTE RESILIENCE AGAINST INFLAMMATORY SWELLING

Rahul Ravindran 1, Drishya Iyer 2, Daniel Lee 2, Meghan Blitchington 3, Christopher Huckstep 2, Riley Telkamp 3, Kevin Telfer 2, Lillian O'Neal 3, Rachel Mintz 2, Deanna Davis 2, Kibeom Park 2, Nadav Yayon 1, Shashi Kumar 2, Alexandre Gallerand 2, Ahmed Hedayat 2, Changqing Ma 2, Mark Hoofnagle 2, Raphael Blain 4, Adrien Hallou 4, Young-Kwon Hong 5, Simon Travis 4, Matthias Friedrich 4, Huaibin Ko 6, Ryan C. Ungaro 6, Chao Zhou 2, Jean-Frédéric Colombel 6, Fiona Powrie 4, Mark Coles 4, Christopher Buckley 4, Bernd Zinselmeyer 2, Gwendalyn Randolph 2, Rafael Czepielewski 3

Affiliations

1 University of Cambridge, Cambridge, United Kingdom

2 Washington University in St. Louis, Saint Louis, United States

3 Augusta University, Augusta, United States

4 University of Oxford, Oxford, United Kingdom

5 Harvard Medical School, Boston, United States

6 Icahn School of Medicine at Mount Sinai, New York City, United States