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PubMed2024

SLC12A1 variant c.1684+1 G>A causes Bartter syndrome type 1 by promoting exon 13 skipping.

BACKGROUND: Bartter syndrome type 1, an autosomal recessive genetic disorder, is caused by pathogenic loss-of-function variants in the SLC12A1 gene. It is characterized by metabolic alkalosis and prenatal-onset polyuria leading to polyhydramnios. METHODS: We identified pathogenic gene in a 12-day-old newborn boy with Bartter syndrome type 1 using whole-exome sequencing. Sanger sequencing validated the identified variants. A minigene assay was performed to investigate the effect of a novel splice site variant on pre-mRNA splicing. RESULTS: We found a compound heterozygous variants in the SLC12A1 gene, consisting of a known pathogenic missense mutation (NM_000338: c.769 G>A; p.Gly257Ser) and a novel splice site variant (c.1684+1 G>A). In silico predictions and an in vitro minigene splicing assay demonstrated that the splicing variant c.1684+1 G>A abolished a consensus splice donor site of SLC12A1 intron 13, resulting in complete exon 13 skipping, translational frameshift, and premature termination codon, ultimately leading to loss of SLC12A1 function. CONCLUSION: Using a cell-based in vitro assay, we revealed the aberrant effect of the pathogenic splicing variant SLC12A1 c.1684+1 G>A on pre-mRNA splicing. Our findings expand the gene mutation spectrum of Bartter syndrome type 1, providing a basis for genetic diagnosis and the development of genetic medicines.

Humans↗

PubMed2026

Integrative analysis and experiment validation of SLC12A8 as a biomarker for the malignant transition from endometriosis to endometriosis associated ovarian cancer.

Endometriosis (EM) is a chronic inflammatory, estrogen‑dependent benign gynecological disorder. A subset of patients with EM may subsequently develop endometriosis‑associated ovarian cancer (EAOC), implying a biological continuum between these two conditions. Nevertheless, the molecular events underlying the progression from benign endometriotic lesions toward EAOC remain incompletely characterized. In this study, transcriptomic datasets retrieved from the GEO database were interrogated through differentially expressed gene screening, functional enrichment analysis, and weighted gene co‑expression network analysis (WGCNA) to identify key genes and pathways relevant to EM and EAOC. Candidate genes were further prioritized by integrating survival analysis via the Kaplan‑Meier Plotter, LASSO regression, random‑forest modeling, and CIBERSORT immune‑infiltration profiling. Loss and gain‑of‑function cellular models were established using siRNA and overexpression plasmids, and in‑vitro functional assays were performed to characterize the phenotypic effects of target genes.We identified several candidate genes associated with EM and EAOC and evaluated their discriminatory performance. Among them, SLC12A8 elevated expression across EM and EAOC tissues and exhibited moderate diagnostic capacity. Higher SLC12A8 expression was also associated with poorer prognosis in EAOC patients. In‑vitro experiments further demonstrated that SLC12A8 modulates proliferation, invasion, and migration in both EM and EAOC cell lines. Collectively, our exploratory research findings support SLC12A8 as a candidate functional mediator and potential biomarker linked to EM‑EAOC pathological progression, thereby extending the mechanistic understanding of these disorders.

Female↗

PubMed2025

Thick Ascending Limb Specific Inactivation of Myh9 and Myh10 Myosin Motors Results in Progressive Kidney Disease and Drives Sex-specific Cellular Adaptation in the Distal Nephron and Collecting Duct.

Our previous work established a role for myosin motor proteins MYH9 and MYH10 in trafficking of thick ascending limb (TAL) cargoes uromodulin and Na+-K+-2Cl- cotransporter NKCC2. We have generated a TAL-specific Myh9&10 conditional knockout (Myh9&10 TAL-cKO) mouse model to determine the cell autonomous roles for MYH9&10 in TAL cargo trafficking and to understand the consequence of TAL dysfunction in adult kidney. Myh9&10 TAL-cKO mice develop progressive kidney disease with pathological tubular injury confirmed by histological changes, tubular injury markers, upregulated endoplasmic reticulum (ER) stress/unfolded protein response, and higher blood urea nitrogen and serum creatinine. However, male mice survive twice as long as female mice. We have determined this sexual dimorphism in morbidity is due to adaptation of the distal nephron and collecting duct in response to TAL dysfunction and lower NKCC2 expression. We demonstrate that this triggers a compensatory mechanism involving sex-specific cellular adaptation within the distal nephron and collecting duct to boost sodium reabsorption. While both sexes overcompensate by activating epithelial sodium channel (ENaC) expression in medullary collecting ducts resulting in hypernatremia, this is initially subdued in male Myh9&10 TAL-cKO mice through higher sodium chloride cotransporter (NCC) expression within the distal nephron. Our results indicate that compromised TAL function ultimately results in maladaptation of medullary collecting duct cells which acquire cortical-like properties including ENaC expression. This work further confirms a cell autonomous role for MYH9&10 in maintenance of NKCC2 expression in the TAL and uncover distal nephron and collecting duct adaptive mechanisms which respond to TAL dysfunction.

Animals↗