Pax4

Pancreatic β-cell failure is a pathological feature in type 1 diabetes. One promising approach involves inducing transdifferentiation of related pancreatic cell types, specifically α cells that produce glucagon. The chemokine stromal cell-derived factor-1 alpha (SDF-1α) is implicated in pancreatic α-to-β like cell transition. Here, the serum level of SDF-1α was lower in T1D with C-peptide loss, the miR-23a was negatively correlated with SDF-1α. We discovered that exosomal miR-23a, secreted from β cells, functionally downregulates the expression of SDF-1α, leading to increased Pax4 expression and decreased Arx expression in vivo...

Maturity-onset diabetes of the young (MODY) encompasses a group of rare monogenic forms of diabetes, with 14 subtypes described in the literature, each with a distinct underlying genetic mutation. We present a case with mutations in 2 different genes that are known to be responsible for MODY. A 33-year-old male individual presented to the endocrinology clinic for evaluation. He was diagnosed with type 2 diabetes mellitus at 13 years of age and was initially treated with insulin, which was subsequently switched to repaglinide and metformin...

AIM: This study aims to investigate the effects of the TCF7L2 rs7903146 and PAX4 rs2233580 (R192H) variants associated with T2D on the therapeutic efficacies of various HAs in patients with T2D after follow-up for 3 years. METHODS: A total of 526 patients who were followed up at the Diabetic Clinic of Siriraj Hospital during 2016-2019 were enrolled. The variants TCF7L2 rs7903146 and PAX4 rs2233580 (R192H) were genotyped using the RNase H2 enzyme-based amplification (rhAmp) technique and the associations between genotypes and glycemic control after treatments with different combinations HA were evaluated using Generalized Estimating Equations (GEE) analysis...

PURPOSE: The objective of this study was to clarify the phenotypic characteristics of monogenic diabetes abnormalities in Thai children with autoantibody-negative insulin. PATIENTS AND METHODS: Two hundred and thirty-one Thai type 1 diabetes (T1D) patients out of 300 participants with recent-onset diabetes were analyzed for GAD65 and IA2 pancreatic autoantibodies. A total of 30 individuals with T1D patients with negative autoantibody were screened for 32 monogenic diabetes genes by whole-exome sequencing (WES)...

In human genome, members of Paired box (PAX) transcription factor family are highly sequence-specific DNA-binding proteins. Among PAX gene family members, PAX4 gene has significant role in growth, proliferation, differentiation, and insulin secretion of pancreatic β-cells. Single nucleotide polymorphisms (SNPs) in PAX4 gene progress in the pathogenesis of various human diseases. Hence, the molecular mechanism of how these SNPs in PAX4 gene significantly progress diseases pathogenesis needs to be elucidated...

OBJECTIVE: Maturity-onset diabetes of the young (MODY) is the most common type of monogenic diabetes. To date, mutations have been identified in 14 different genes of patients with a clinical diagnosis of MODY. This study screened mutations in 14 MODY-related genes and the regulator factor X6 (RFX6) gene in children. MATERIALS AND METHODS: The presence of clinical features of MODY and negative results for three autoantibody markers of T1DM in children and adolescents were used as inclusion criteria for genetic testing...

BACKGROUND: Unlike most free-living platyhelminths, catenulids, the sister group to all remaining flatworms, do not have eyes. Instead, the most prominent sensory structures in their heads are statocysts or sensory pits. The latter, found in the family Stenostomidae, are concave depressions located laterally on the head that represent one of the taxonomically important traits of the family. In the past, the sensory pits of flatworms have been homologized with the cephalic organs of nemerteans, a clade that occupies a sister position to platyhelminths in some recent phylogenies...

Enteroendocrine cells (EECs) are hormone-producing cells residing in the epithelium of stomach, small intestine (SI), and colon. EECs regulate aspects of metabolic activity, including insulin levels, satiety, gastrointestinal secretion, and motility. The generation of different EEC lineages is not completely understood. In this work, we report a CRISPR knockout screen of the entire repertoire of transcription factors (TFs) in adult human SI organoids to identify dominant TFs controlling EEC differentiation...

The coding variant (p.Arg192His) in the transcription factor PAX4 is associated with an altered risk for type 2 diabetes (T2D) in East Asian populations. In mice, Pax4 is essential for beta cell formation but its role on human beta cell development and/or function is unknown. Participants carrying the PAX4 p.His192 allele exhibited decreased pancreatic beta cell function compared to homozygotes for the p.192Arg allele in a cross-sectional study in which we carried out an intravenous glucose tolerance test and an oral glucose tolerance test...

OBJECTIVES: PAX4 (Paired box 4), a transcription factor crucial in pancreatic beta cell development and function, is a rare cause of maturity-onset diabetes of the young (MODY). What is new? A novel PAX4 variant is verified by family segregation study to be likely pathogenic. A child below 10 years of age diagnosed to have PAX4-MODY, differing from previously reported paediatric cases diagnosed in adolescence. CASE PRESENTATION: A child with diabetes diagnosed at age 8 years, harbored a PAX4 variant, c...

Paired box 4 (PAX4) is a pivotal transcription factor involved in pancreatogenesis during embryogenesis, and in adults, it is key for β-cell proliferation and survival. Additionally, PAX4 also functions as a tumor suppressor protein in human melanomas. The present study demonstrates the production of bioactive recombinant human PAX4 transcription factor. At first, the inserts (PAX4 protein-coding sequence having tags at either ends) were cloned in an expression vector to give rise to pET28a(+)-HTN-PAX4 and pET28a(+)-PAX4-NTH genetic constructs, and these were then transformed into Escherichia coli (E...

BACKGROUND: Maturity-onset diabetes of the young (MODY) is a monogenic genetic disease often clinically misdiagnosed as type 1 or type 2 diabetes. MODY type 9 (MODY9) is a rare subtype caused by mutations in the PAX4 gene. Currently, there are limited reports on PAX4 -MODY, and its clinical characteristics and treatments are still unclear. In this report, we described a Chinese patient with high autoimmune antibodies, hyperglycemia and a site mutation in the PAX4 gene. CASE SUMMARY: A 42-year-old obese woman suffered diabetes ketoacidosis after consuming substantial amounts of beverages...

Previous studies indicated that ductal cells can contribute to endocrine neogenesis in adult rodents after alpha cells convert into beta cells. This can occur through Pax4 mis-expression in alpha cells or through long-term administration of gamma-aminobutyric acid (GABA) to healthy mice. GABA has also been reported to increase the number of beta cells through direct effects on their proliferation, but only in specific genetic mouse backgrounds. To test whether GABA induces neogenesis of beta cells from ductal cells or affects pancreatic cell proliferation, we administered GABA or saline over 2 or 6 months to Sox9CreER;R26RYFP mice in which 60-80% of large or small ducts were efficiently lineage labeled...

OBJECTIVE: To evaluate the Type 2 Diabetes (T2D) risk variants in the Pashtun ethnic population of Khyber Pakhtunkhwa using nascent whole-exome sequencing (WES) to better understand the pathogenesis of this complex polygenic disorder. METHODOLOGY: A total of 100 confirmed patients with T2D of Pashtun ethnicity were included in the study, DNA was extracted from whole blood samples, and paired-end libraries were prepared using the Illumina Nextera XT DNA library kit carefully following the manufacturer's instructions...

Proteasome activity is crucial for cellular integrity, but how tissues adjust proteasome content in response to catabolic stimuli is uncertain. Here, we demonstrate that transcriptional coordination by multiple transcription factors is required to increase proteasome content and activate proteolysis in catabolic states. Using denervated mouse muscle as a model system for accelerated proteolysis in vivo , we reveal that a two-phase transcriptional program activates genes encoding proteasome subunits and assembly chaperones to boost an increase in proteasome content...

Paired box 4 (Pax4) is a key transcription factor involved in the embryonic development of the pancreatic islets of Langerhans. Consisting of a conserved paired box domain and a homeodomain, this transcription factor plays an essential role in early endocrine progenitor cells, where it is necessary for cell-fate commitment towards the insulin-secreting β cell lineage. Knockout of Pax4 in animal models leads to the absence of β cells, which is accompanied by a significant increase in glucagon-producing α cells, and typically results in lethality within days after birth...

Direct lineage reprogramming of one somatic cell into another without transitioning through a progenitor stage has emerged as a strategy to generate clinically relevant cell types. One cell type of interest is the pancreatic insulin-producing β cell whose loss and/or dysfunction leads to diabetes. To date it has been possible to create β-like cells from related endodermal cell types by forcing the expression of developmental transcription factors, but not from more distant cell lineages like fibroblasts...

Pancreatic ɛ-cells producing ghrelin are one type of endocrine cell found in islets, which have been shown to influence other intra-islet cells, especially in regulating the function of β cells. However, the role of such cells during β-cell regeneration is heretofore unknown. Here, using a zebrafish nitroreductase (NTR)-mediated β-cells ablation model, we uncover that ghrelin-positive ɛ-cells in the pancreas act as contributors to neogenic β-cells after extreme β-cell loss...

During differential diagnosis of diabetes mellitus, the greatest difficulties are encountered with young patients because various types of diabetes can manifest themselves in this age group (type 1, type 2, and monogenic types of diabetes mellitus, including maturity-onset diabetes of the young (MODY)). The MODY phenotype is associated with gene mutations leading to pancreatic-β-cell dysfunction. Using next-generation sequencing technology, targeted sequencing of coding regions and adjacent splicing sites of MODY-associated genes ( HNF4A , GCK , HNF1A , PDX1 , HNF1B , NEUROD1 , KLF11 , CEL , PAX4 , INS , BLK , KCNJ11 , ABCC8 , and APPL1 ) was carried out in 285 probands...

Nemaline myopathies (NM) are a group of congenital myopathies that lead to muscle weakness and dysfunction. While 13 genes have been identified to cause NM, over 50% of these genetic defects are due to mutations in nebulin (NEB) and skeletal muscle actin (ACTA1), which are genes required for normal assembly and function of the thin filament. NM can be distinguished on muscle biopsies due to the presence of nemaline rods, which are thought to be aggregates of the dysfunctional protein. Mutations in ACTA1 have been associated with more severe clinical disease and muscle weakness...