Alterations in SLC4A2, SLC26A7 and SLC26A9 Drive Acid–Base Imbalance in Gastric Neuroendocrine Tumors and Uncover a Novel Mechanism for a Co-Occurring Polyautoimmune Scenario

Abstract

Autoimmune polyendocrine syndrome (APS) is assumed to involve an immune system malfunction and entails several autoimmune diseases co-occurring in different tissues of the same patient; however, they are orphans of its accurate diagnosis, as its genetic basis and pathogenic mechanism are not understood. Our previous studies uncovered alterations in the ATPase H+/K+ Transporting Subunit Alpha (ATP4A) proton pump that triggered an internal cell acid–base imbalance, offering an autoimmune scenario for atrophic gastritis and gastric neuroendocrine tumors with secondary autoimmune pathologies. Here, we propose the genetic exploration of APS involving gastric disease to understand the underlying pathogenic mechanism of the polyautoimmune scenario. The whole exome sequencing (WES) study of five autoimmune thyrogastric families uncovered different pathogenic variants in SLC4A2, SLC26A7 and SLC26A9, which cotransport together with ATP4A. Exploratory in vitro studies suggested that the uncovered genes were involved in a pathogenic mechanism based on the alteration of the acid–base balance. Thus, we built a custom gene panel with 12 genes based on the suggested mechanism to evaluate a new series of 69 APS patients. In total, 64 filtered putatively damaging variants in the 12 genes of the panel were found in 54.17% of the studied patients and none of the healthy controls. Our studies reveal a constellation of solute carriers that co-express in the tissues affected with different autoimmune diseases, proposing a unique genetic origin for co-occurring pathologies. These results settle a new-fangled genetics-based mechanism for polyautoimmunity that explains not only gastric disease, but also thyrogastric pathology and disease co-occurrence in APS that are different from clinical incidental findings. This opens a new window leading to the prediction and diagnosis of co-occurring autoimmune diseases and clinical management of patients.

A High-Quality Chromosome-Level Genome Assembly of a Snail Cipangopaludina cathayensis (Gastropoda: Viviparidae)

“…Figure 4C,D show the GO and KEGG enrichment of the positive selective genes, respectively. Five putative genes that appeared to be positively selected in C. cathayensis In C. cathayensis, we found an expansion gene slc4a2 and a positive gene b3galt6, which were, respectively, related to digestion [49] and bone development [50]. These findings may suggest that C. cathayensis has strong digestive and shell formation abilities in order to adapt well to various environments.…”

Prognostic 7-SLC-Gene Signature Identified via Weighted Gene Co-Expression Network Analysis for Patients with Hepatocellular Carcinoma

“…Te SLC4A2 gene encodes bicarbonate-chloride anion exchange protein 2 (AE2), which mediates proton leakage across the Golgi membrane and allows the Golgi apparatus to act as a proton reservoir in cancer cells, thereby regulating the pH microenvironment of TCS and promoting tumourigenesis and progression [38]. Malfunction of the acid-base homeostasis caused by SLC4A2 can also afect mitochondrial gradients and trigger ROS damage, leading to apoptosis, proliferation, and morphological alterations [39]. SLC9A3R1 encodes the sodium-hydrogen exchange regulator protein (NHERF1) and directly interacts with the PTEN pathway, and its deletion results in increased cell proliferation and Akt activation.…”

Update in Molecular Aspects and Diagnosis of Autoimmune Gastritis

“…These genes are responsible for immune regulation and include protein tyrosine phosphatase non-receptor type 22 (PTPN22), polyribonucleotide nucleotidyltransferase 1 (PNPT1), major histocompatibility complex class II, DQ beta 1 (HLA-DQB1), interleukin 2 receptor subunit alpha (IL2RA), and the AIRE genes. A study using whole exome sequencing to investigate five families with autoimmune thyrogastric disorders identified distinct pathogenic variants in solute carrier family 4 member 2 (SLC4A2), solute carrier family 26 member 7 (SLC26A7), and member 9 (SLC26A9) genes [10]. These solute carriers play a pivotal role in modulating the acid-base balance within parietal cells, thus serving as essential contributors to the H+/K+ exchange.…”