<i><scp>INPP</scp>4B</i> overexpression and <i>c‐<scp>KIT</scp></i> downregulation in human achalasia

Bonora, Elena; Bianco, Francesca; Stanzani, Agnese; Giancola, Fiorella; Astolfi, Annalisa; Indio, Valentina; Evangelisti, Camilla; Martelli, Alberto M.; Boschetti, Elisa; Lugaresi, Marialuisa; Ioannou, Alexandros; Torresan, F.; Stanghellini, Vincenzo; Clavenzani, Paolo; Seri, Marco; Moonen, An; Beek, Karen Van; Wouters, Mira M.; Boeckxstaens, Guy E.; Zaninotto, Giovanni; Mattioli, Sandro; Giorgio, Roberto De

doi:10.1111/nmo.13346

Cited by 7 publications

(4 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…INPP4B overexpression is associated with human achalasia, which is a rare motility disorder characterized by myenteric neuron and interstitial cells of Cajal abnormalities 82 . Depleting INPP4B by in utero electroporation in mice suppressed medially directed callosal axon formation and significantly attenuated the formation of pyramidal neurons and axon polarization in cortical neurons during cortical development 83 .…”

Section: Discussionmentioning

confidence: 99%

Exome sequencing of families from Ghana reveals known and candidate hearing impairment genes

et al. 2022

View full text Add to dashboard Cite

We investigated hearing impairment (HI) in 51 families from Ghana with at least two affected members that were negative for GJB2 pathogenic variants. DNA samples from 184 family members underwent whole-exome sequencing (WES). Variants were found in 14 known non-syndromic HI (NSHI) genes [26/51 (51.0%) families], five genes that can underlie either syndromic HI or NSHI [13/51 (25.5%)], and one syndromic HI gene [1/51 (2.0%)]. Variants in CDH23 and MYO15A contributed the most to HI [31.4% (16/51 families)]. For DSPP, an autosomal recessive mode of inheritance was detected. Post-lingual expression was observed for a family segregating a MARVELD2 variant. To our knowledge, seven novel candidate HI genes were identified (13.7%), with six associated with NSHI (INPP4B, CCDC141, MYO19, DNAH11, POTEI, and SOX9); and one (PAX8) with Waardenburg syndrome. MYO19 and DNAH11 were replicated in unrelated Ghanaian probands. Six of the novel genes were expressed in mouse inner ear. It is known that Pax8-/- mice do not respond to sound, and depletion of Sox9 resulted in defective vestibular structures and abnormal utricle development. Most variants (48/60; 80.0%) have not previously been associated with HI. Identifying seven candidate genes in this study emphasizes the potential of novel HI genes discovery in Africa.

show abstract

Section: Discussionmentioning

confidence: 99%

Exome sequencing of families from Ghana reveals known and candidate hearing impairment genes

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Intraoperative manometry taught us how to abolish the lower esophageal sphincter to “cure” dysphagia and also how to tailor the Dor fundoplication, to be effective in preventing postmyotomy GERD,23–26 but not be obstructive. Dysphagia is the only clinical consequence of the irreversible damage of myenteric neurons and interstitial cells of Cajal, leading to deranged/absent peristalsis and lack of relaxation of the lower esophageal sphincter disease43; its disappearance leads us to consider the disease as “cured.” Intraoperative manometry indicated that the manometric 0 corresponding to the total abolition of the Lower Esophago-Gastric Sphincter is achieved only after: (1) the complete separation of the U and sling fibers far down (at least for 3 cm) the angle of His; (2) the limited (5–6 cm) upward extension of the myotomy, not to surpass the apex of the hiatus, so to allow a convenient stitch between the apex of the myotomy and the Dor fundoplication; (3) the meticulous section of every thin muscular bridge between the 2 edges of the myotomy. Intraoperative manometry equally taught us to perform the Dor fundoplication with the following technical characteristics: (1) it must be totally abdominal, at least 7 to 8 cm long (5 esophageal+3 gastric myotomy); (2) sutures between the fundus and the 2 edges of the myotomy are applied 1 cm apart, and at least the top 4 are placed fundus-myotomy edge-hiatus; the final Dor pressure is higher if the short gastric vessels are not divided.…”

Section: Discussionmentioning

confidence: 99%

Outcomes of Heller Myotomy for Esophageal Achalasia

et al. 2022

View full text Add to dashboard Cite

Objective: To provide information on long-term outcomes of Heller myotomy for esophageal achalasia with or without an antireflux fundoplication. Background: Since the adoption of the Heller myotomy, surgeons have modified the original technique in order to balance the cure of dysphagia and the consequent cardial incontinence. Methods: Totally, 470 patients underwent primary Heller myotomy between 1955 and 2020. A long abdominal myotomy (AM) was performed in 83 patients, the Ellis limited transthoracic myotomy (TM) in 30, the laparotomic Heller-Dor (L-HD) in 202, the videolaparoscopic Heller-Dor (VL-HD) in 155. The HD was performed under intraoperative manometric assessment. Starting on 1973 these patients underwent a prospective follow-up program of timed lifelong clinical, radiological, endoscopic evaluations. Results: Median follow-up time was 23.06 years [interquantile range (IQR): 15.04–32.06] for AM, 29.22 years (IQR: 13.46–40.17) for TM, 14.85 years (IQR: 11.05–21.56) for L-HD and 7.51 years (IQR: 3.25–9.60) for VL-HD. In AM, relapse of dysphagia occurred in 25/71 (35.21%), in TM in 11/30 (36.66%), in LH-D in 10/201 (4.97%), in VL-HD in 3/155 (1.93%). Erosive-ulcerative esophagitis was diagnosed for AM in 28.16%, for TM in 30%, for L-HD in 8.45%, for VL-HD in 2.58%. Overall, the outcome was satisfactory in 52.11% for AM, 41.9% for TM, 89.05% for L-HD, 96.12% for VL-HD. Conclusions: The Dor fundoplication drastically reduces postmyotomy gastroesophageal reflux. The Heller-Dor operation is a competitive option for the cure of esophageal achalasia if this operation is performed according to the rules of surgical physiology learned by means of intraoperative manometry.

show abstract

“…Previous studies demonstrated various inflammatory cells infiltrated in LES, such as T cells, eosinophils, and mast cells [2][3][4] . Whole-exome and RNA sequencing of achalasia patients identified achalasia-associated loci enriched for immunological and neurological processes 5,6 , suggesting that the immune response may be a critical factor in the disease. However, most studies have focused on the proportion of immune cells and inflammatory mediators without exploring the underlying mechanism.…”

mentioning

confidence: 99%

A single-cell transcriptional landscape of immune cells shows disease-specific changes of T cell and macrophage populations in human achalasia

et al. 2023

View full text Add to dashboard Cite

Achalasia is a rare motility disorder of the esophagus caused by the gradual degeneration of myenteric neurons. Immune-mediated ganglionitis has been proposed to underlie the loss of myenteric neurons. Here, we measure the immune cell transcriptional profile of paired lower esophageal sphincter (LES) tissue and blood samples in achalasia and controls using single-cell RNA sequencing (scRNA-seq). In achalasia, we identify a pattern of expanded immune cells and a specific transcriptional phenotype, especially in LES tissue. We show C1QC+ macrophages and tissue-resident memory T cells (TRM), especially ZNF683+ CD8+ TRM and XCL1+ CD4+ TRM, are significantly expanded and localized surrounding the myenteric plexus in the LES tissue of achalasia. C1QC+ macrophages are transcriptionally similar to microglia of the central nervous system and have a neurodegenerative dysfunctional phenotype in achalasia. TRM also expresses transcripts of dysregulated immune responses in achalasia. Moreover, inflammation increases with disease progression since immune cells are more activated in type I compared with type II achalasia. Thus, we profile the immune cell transcriptional landscape and identify C1QC+ macrophages and TRM as disease-associated immune cell subsets in achalasia.

show abstract

INPP4B overexpression and c‐KIT downregulation in human achalasia

Abstract: The identification of altered gene expression, including INPP4B, a regulator of the Akt pathway, highlights novel signaling pathways involved in the neuronal and ICC changes underlying primary achalasia.

Cited by 7 publications

References 34 publications

Exome sequencing of families from Ghana reveals known and candidate hearing impairment genes

Exome sequencing of families from Ghana reveals known and candidate hearing impairment genes

Outcomes of Heller Myotomy for Esophageal Achalasia

A single-cell transcriptional landscape of immune cells shows disease-specific changes of T cell and macrophage populations in human achalasia

Contact Info

Product

Resources

About