SLC26A4 Gene Research Articles

Forced Overexpression and Knockout Analysis of SLC30A and SLC39A Family Genes Suggests Their Involvement in Establishing Resistance to Cisplatin in Human Cancer Cells

Abstract: The metabolism of zinc and manganese plays a pivotal role in cancer progression by mediating cancer cell growth and metastasis. The SLC30A family proteins SLC30A3 and SLC30A10 mediate the efflux of zinc, manganese, and probably other transition element ions outside the cytoplasm to the extracellular space or into intracellular membrane compartments. The SLC39A family members SLC39A8 and SLC39A14 are their functional antagonists that transfer these ions into the cytoplasm. Recently, the SLC30A10 gene was suggested as a promising methylation biomarker of colorectal cancer. Here, we investigated whether forced overexpression or inactivation of SLC30A and SLC39A family genes has an impact on the phenotype of cancer cells and their sensitivity to cancer therapeutics. In the human colon adenocarcinoma HCT-15 and duodenal adenocarcinoma HuTu80 cell lines, we generated clones with knockouts of the SLC39A8 and SLC39A14 genes and forced overexpression of the SLC30A3, SLC30A10, and SLC39A8 genes. Gene expression in the mutant and control cells was assessed by RNA sequencing. The cell growth rate, mitochondrial activity, zinc accumulation, and sensitivity to the drugs cetuximab and cisplatin were investigated in functional tests. Overexpression or depletion of SLC30A or SLC39A family genes resulted in the deep reshaping of intracellular signaling and provoked hyperactivation of mitochondrial respiration. Variation in the expression of the SLC30A/SLC39A genes did not increase the sensitivity to cetuximab but significantly altered the sensitivity to cisplatin: overexpression of SLC30A10 resulted in an ~2.7–4 times increased IC50 of cisplatin, and overexpression of SLC30A3 resulted in an ~3.3 times decreased IC50 of cisplatin. The SLC30A/SLC39A genes should be considered as potential cancer drug resistance biomarkers and putative therapeutic targets.

SLC2A1 variants cause late-onset epilepsy and the genetic-dependent stage feature

BackgroundThe SLC2A1 gene plays a vital role in brain energy metabolism. SLC2A1 variants have been reported to be associated with early-onset refractory seizures. This study aims to explore the association between the SLC2A1 gene and late-onset epilepsy.MethodsTrios-based whole-exome sequencing was performed on patients with epilepsy without acquired etiologies. The pathogenicity of the variants was assessed according to the American College of Medical Genetics and Genomics (ACMG) guidelines.ResultsA total of 14 heterozygous SLC2A1 variants were identified in 16 unrelated families. The variants were evaluated as “pathogenic” or “likely pathogenic” according to the ACMG guidelines. Ten cases (62.5%) presented with infantile onset seizures and developmental delay/intellectual disability and were diagnosed with developmental and epileptic encephalopathy (DEE). The other six cases (37.5%) exhibited late-onset seizures and normal development. They were diagnosed with idiopathic partial epilepsy (n = 2) or idiopathic generalized epilepsy (n = 4). Further analysis showed that DEE-associated variants tended to cluster in the transmembrane region, whereas the mild epilepsy-associated variants tended to locate in regions outside the transmembrane region, suggesting a potential molecular sub-regional effect. A total of 15 cases had delayed diagnosis, with the longest delay being 22 years. The SLC2A1 expression stage, which is expressed at relatively high level throughout the whole life span, from the embryonic to adult stages with two peaks at approximately four and 14 years, is generally consistent with the seizure onset age. In addition, patients with early-onset age had variants that were potentially associated with severe damage, suggesting a potential correlation between the age of disease onset and the damaging effects of the variants.ConclusionsSLC2A1 variants are associated with late-onset epilepsy, which is consistent with the genetic-dependent stage feature of SLC2A1. Early genetic diagnosis is important for treatment of patients with SLC2A1 variants.

Marked microcytosis and increased transferrin saturation: Think about variants in SLC11A2 (DMT1)

Congenital microcytic anemias are rare diseases associated with decreased hemoglobin synthesis and red blood cells of low corpuscular volume. DMT1/NRAMP2 is a highly conserved divalent cation transporter encoded by the SLC11A2 gene, expressed at the membrane of various cells. It ensures ferrous iron absorption from the apical membrane of enterocytes, iron recovery from urine by renal tubules, and acidified endosome uptake after transferrin internalization. Pathogenic DMT1 variants have been described in 10 individuals to date, associated with recessive hypochromic anemia and iron overload. Herein, we report a new variant of SLC11A2 (c.469A>G, p.Ile157Val) compound with known p.Arg416Cys associated with a frankly microcytic anemia and increased transferrin saturation. The clinical picture observed in the patient was exceptionally mild, extending the field of the DMT1 phenotypes to borderline anemias.

The Benefits of Whole-Exome Sequencing in the Differential Diagnosis of Hypophosphatasia

Hypophosphatasia (HPP) is a rare inherited disorder characterized by the decreased activity of tissue-nonspecific alkaline phosphatase (TNSALP), caused by mutations in the ALPL gene. The aim of this study was to conduct differential diagnostics in HPP patients using whole-exome sequencing (WES). The medical records of HPP patients and the genetic testing of the ALPL gene were reviewed. Seven patients were recruited and underwent WES using the Illumina or MGI sequencing platforms. All of the exome samples were matched onto a GRCh38.p13 reference genome assembly by using the Genome Analysis ToolKit (GATK) and the BWA MEM read aligner. We present the clinical and molecular findings of the seven patients referred for genetic analyses due to a clinical and biochemical suspicion of HPP. In two patients out of three (with identified heterozygous variants in the ALPL gene), we also identified c.682T>A in exon 3 of the WNT10A gene and c.3470del in exon 23 of the SMC1A gene variants for the first time. In four patients, variants in the ALPL gene were not detected, but WES allowed us to identify for the first time rare variants (c.5651A>C in exon 36 of the TRIO gene, c.880T>G in exon 6 of the TRPV4 gene, c.32078-1G>T in intron 159 of the TTN gene, c.47720_47721del in exon 235 of the TTN gene, and c.1946G>A in exon 15 of the SLC5A1 gene) and to conduct differential diagnostics with HPP. Using WES, for the first time, we demonstrate the possibility of early differential diagnostics in HPP patients with other rare genetic diseases.

Thiamine-Responsive Megaloblastic Anemia (TRMA) Syndrome mimicking myelodysplastic neoplasm (MDS)

Thiamine-responsive megaloblastic anemia syndrome (TRMA) is a rare autosomal recessive disease with a homozygous or compound-heterozygous mutation in the SLC19A2 gene characterized by megaloblastic anemia, diabetes mellitus (DM), and sensorineural hearing-loss with onset in childhood. Folic acid and vitamin B12 in serum are normal with dysplastic erythropoiesis in the bone marrow often mimicking myelodysplastic neoplasms (MDN) as a potential differential diagnosis. Thiamine substitution leads to normalization of anemia, without effects on hearing-loss or DM. We report about a 38-year-old male patient, presented with a 12-year history of anemia, insulin dependent DM, optic neuropathy and a cataract since early childhood. The laboratory showed megaloblastic anemia. Other values were normal. The bone marrow smear showed dysplastic erythropoiesis with megaloblastic changes, and normal findings in cytogenetic and molecular genetic examinations. Next-generation sequencing based diagnostics revealed a heterozygous missense variant in the SLC19A2 gene on the maternal allele and a 3.4 Mb inversion in the chromosomal region 1q24.2 with breaking points in FAM78B and SLC19A2 on the paternal allele. Treatment with oral thiamine 100 mg daily was initiated, and 12 weeks later Hb levels and bone marrow morphology had normalized. Late-onset TRMA should be considered in adult patients with indicative comorbidities and a typical phenotype, which may mimic features of MDS.

The contribution of iron metabolism to heart failure: a haematological and biochemical perspective

Abstract Introduction Heart failure (HF) can be influenced by diverse modulators, such as genes involved in iron metabolism - HFE, SLC40A1 and TMPRSS6, and haematological and biochemical parameters - serum iron, ferritin, transferrin saturation, mean corpuscular volume (MCV) and Red Cell Distribution Width (RDW). Objectives To investigate the association of genetic variants in the HFE gene [C282Y (rs1800562) and H63D (rs1799945)], SLC40A1 (rs1439816 and rs2304704) and TMPRSS6 (rs855791) with haematological parameters and biochemical biomarkers of iron metabolism in HF and in its various forms of presentation [preserved Ejection Fraction-HFpEF and non-preserved Ejection Fraction-HFnpEF (middly reduced + reduced)], in each sex. Methods 301 individuals with HF were studied (141 men and 160 women), with a median age of 80 years (min=31 and max=99) and a median body mass index (BMI) of 25.90 kg/m2 (min=16.50 and max=47.30). Multiplex PCR-ARMS technique was used to analyze the HFE gene variants (C282Y and H63D) and Endpoint Genotyping was used for the remaining variants. Statistical analysis was carried out using SPSS software, version 28.0, with a statistical significance level of p<0.05. Results The presence of indicators of iron deficiency anaemia was verified in the haematological and biochemical parameters in our population of HF. Significant differences were found in serum iron values in the presence of the mutant allele for the three genes studied: 1)in the H63D (p=0.006) for females, and more particularly in females with HFnpEF (p=0.020); 2) in the rs1439816 for males (p=0.035) and more particularly in males with HFpEF (p=0.036); and 3) in the rs855791 for males (p=0.018). As for ferritin, significant differences were found in the presence of the mutant allele for the rs2304704 (p=0.001) in females. For transferrin saturation, significant differences were found in the presence of the mutant allele for the three genes studied: 1) in the H63D (p=0.013) for females, more specifically in females with HFpEF (p=0.043); 2) in the rs1439816 in males (p=0.037); and 3) in the rs855791 in females (p=0.034), particularly in females with HFpEF (p=0.023), and in males (p=0.032), particularly in males with HFpEF (p=0.037). Analyzing the MCV, there were statistically significant differences in the presence of the mutant allele for the rs2304704 (p=0.012) in females, particularly in those with HFpEF (p<0.001). Regarding RDW, significant differences were found in the presence of the mutant allele of the C282Y polymorphism in females with HFpEF (p=0.048). Conclusion Ferropenic anaemia highly prevalent in this population with HF. All the genes analyzed contribute to the modulation of the analyzed parameters/biomarkers, however, the SLC40A1 gene showed greater modulating capacity. Genetic modulation was more relevant in HFpEF women, suggesting that this sex is the most susceptible to genetic modulation.

Identifying DNA Variants in a Turkish Cohort with Inner Ear Anomalies.

To determine the genetic causes of sensorineural hearing loss (SNHL) associated with inner ear anomalies, 11 unrelated Turkish individuals diagnosed with SNHL and an inner ear anomaly using temporal bone computed tomography and inner ear magnetic resonance imaging underwent exome or whole genome sequencing to identify underlying genetic defects. None of the individuals was diagnosed with a recognized syndrome. Four of the 11 probands were homozygous for SLC26A4 variants, c.283G>A, c.845G>A, c.1061T>C, and c.1198delT. Another proband was homozygous for a TECTA variant, c.4163G>A. Patients with variants of the SLC26A4 gene had bilateral enlarged vestibular aqueduct, bilateral incomplete partition type 2 anomaly, bilateral hypoplastic cochlea and bilateral enlarged vestibular aqueduct plus hypoplastic cochlea anomaly. Patients with the variant TECTA gene had bilateral hypoplastic cochlea. This study identified variants of SLC26A4 in 36% of probands with inner ear anomalies. While we identified a variant of the TECTA gene in a proband with cochlear hypoplasia, further studies are needed to see if TECTA variants can cause cochlear malformations.

7494 Glycerol Phenylbutyrate Treatment of Two Patients with Monocarboxylate Transporter 8 Deficiency

Abstract Disclosure: A. Zung: None. N. Sonntag: None. U. Schweizer: None. E. Banne: None. D. Braun: None. Context: Monocarboxylate transporter 8 (MCT8) deficiency is a rare genetic disease that leads to severe global developmental delay. MCT8 facilitates thyroid hormone (TH) transport across the cell membrane, and the serum TH profile is characterized by high T3 and low T4 levels. Currently, the two thyromimetic agents 3,5-diiodothyropropionic acid (DITPA) and triiodothyroacetic acid (TRIAC) have been evaluated in the treatment of these patients, as they both partially restore intracellular TH action independent of MCT8. Recent studies have shown that the chemical chaperone sodium phenylbutyrate (NaPB) restored mutant MCT8 function and increased TH content in patient-derived induced pluripotent stem cells, making it a potential treatment for MCT8 deficiency. Objective: We aimed to assess the efficacy and safety of glycerol phenylbutyrate (GPB) in MCT8 deficiency. Methods: We treated two monozygotic twins aged 14.5 years with MCT8 deficiency due to P321L mutation with escalating doses of GPB over 13 months. We recorded TH, serum markers of peripheral hyperthyroidism, vital signs, anthropometric measurements and neurocognitive functions by several neurodevelopment validated tests. Resting metabolic rate (RMR) was measured by indirect calorimetry. Serum metabolites of GPB were monitored as a safety measure. In-vitro effects of NaPB were evaluated in MDCK1 cells stably expressing the MCT8P32[1]L mutation. Results: NaPB restored mutant MCT8 expression in MDCK1 cells and increased T3 transport into cells carrying the P321L mutation. GPB treatment yielded a dose-dependent decrease in FT3 and an increase in FT4 serum levels. The patients showed an elevation in cholesterol levels in parallel with GPB dose, but sex-hormone binding protein (SHBG), another marker of peripheral hyperthyroidism was not affected. The patients showed a significant weight gain simultaneously with a reduction in RMR. Only minor neuro-cognitive improvement was observed, mainly in hyperreflexia score, slight improvement in gross motor functions and a mild progression in cognitive functions. Serum metabolites of GPB did not exceed the toxic range but elevated liver transaminases restricted the dose intensification of GPB. Conclusions: In the first report of GPB treatment in MCT8 deficiency patients we found an improvement in TH profile and body-mass index (BMI). The reduction in T3 levels could contribute to the remarkable increase in BMI-SDS, since various aspects of peripheral hyperthyroidism in MCT8 deficiency, including poor weight gain, were attributed to elevated T3. The limited effects of GPB treatment on cognitive and motor functions can derive from the advanced age of the patients at the time of the intervention. Presentation: 6/2/2024

12279 Molecular Strategy And Genetic Characterization Of A Large Cohort Of Pediatric Patients With Hereditary Hypophosphatemic Rickets: Advantages Of Next Generation Sequencing

Abstract Disclosure: N. Perez Garrido: None. P. Ramirez: None. G.L. Viterbo: None. M. del Pino: None. S. Abbate: None. N.I. Saraco: None. F. Tesan: None. M. Ciaccio: None. V. Fano: None. A. Belgorosky: None. R. Marino: None. Background: Hereditary hypophosphatemic rickets (HHR) is a group of rare disorders characterized by renal phosphate wasting and impairment of vitamin D metabolism. Different genetic defects can cause HHR, although they share similar clinical, radiological and biochemical features. Dominant X-linked HR (XLHR) is the most frequent form (1/ 20,000) caused by inactivating variants in PHEX gene. As affected individuals present with a broad phenotypic spectrum next generation sequencing (NGS) represent a useful tool for molecular diagnosis characterization. Aim: To report a molecular strategy and genetic characterization of a large cohort of pediatric patients with HHR followed in a single tertiary institution. Patients and Methods: We analyzed 77 affected patients from 60 non related families (and 58 parents) sent to our laboratory for molecular genetic testing under suspicion of HHR based on clinical, radiological and laboratory studies.In patients without hypercalciuria, Sanger sequencing of PHEX gene was initially performed. In female cases in which no alteration was detected, MLPA analysis was used to detect copy number variations. A group of patients with no proven variations in PHEX gene and those with hypercalciuria were analyzed using a NGS custom panel including 14 related genes. Results: Of the total 60 non related cases a pathogenic variant was found in 52 (87%). Regarding PHEX gene analysis, a pathogenic variant was found in 48/60 (80%), 27 were sporadic and 21 familial cases. Forty-one different pathogenic variants were found (5 gross deletions, 13 nonsense, 9 frameshift, 5 splice-site and 9 missense) distributed throughout the gene with higher prevalence from exon 15 to 22. 18/41 (44%) of variants were novel. RNA analysis was performed in 2 novel splice variants (c.849G>A-p.Glu283Glu and c.1586+6T>A) in which an abnormal splicing was confirmed.We found a pathogenic variant in 5/9 cases analyzed by NGS. Three of them in SLC34A3 gene (2 homozygous, 1 compound heterozygous), 1 in ENPP1 gene (compound heterozygous) and 1 in PHEX gene non-detected by Sanger sequencing. Discussion: This molecular strategy, along with a careful clinical and biochemical selection of patients, allowed us to perform genetic diagnosis in 87 % of non-related families. This study reports 21 novel pathogenic variants and it shows the greatest genetic characterization in pediatric HHR patients in Argentine population. The results obtained confirmed that PHEX is the most responsible gene for HHR phenotype, as previously described. By NGS, less common forms of rickets could be detected. Among them, the most frequent was HHR with hypercalciuria due to recessive mutations in SLC34A3 gene. NGS studies represent a useful tool, especially in those complex cases, to reach an accurate diagnosis, and they contribute to improve long term follow up of patients and genetic counseling. Presentation: 6/2/2024

8759 Mild Iodine Deficiency During Pregnancy Impairs Hypothalamus-Pituitary-Thyroid Function Programing of the Adult Male Offspring

Abstract Disclosure: M. Oliveira: None. E. Tavares: None. G. Henrique: None. J. Pinto: None. C. Serrano-Nascimento: None. Introduction: Iodine plays a crucial role in the biosynthesis of thyroid hormones and is essential for proper thyroid embryonic development. While severe iodine deficiency during pregnancy and lactation has well-documented deleterious effects, the consequences of mild iodine deficiency (MID) remain not fully understood. MID during pregnancy is a reality in numerous countries, even in regions with seemingly adequate iodine supply in the diet. Previous studies have highlighted the adverse impact of MID on neurological development in offspring, but comprehensive data on thyroid function, particularly in progeny at different developmental stages, are lacking. This study aimed to investigate the repercussions of MID during pregnancy on the programming of thyroid dysfunctions during adulthood. Methods: Female CD1 mice were subjected to iodine-deficient animal chow and iodine-supplemented water, either at normal (NI; 0.2 mg/L) or mild iodine deficiency (MID; 0.8 mg/L) levels during pregnancy. Gene and protein expression in the hypothalamus, pituitary, and thyroid of adult male offspring animals (PND90) were evaluated using qPCR and Western blotting. Additionally, this study explored MID-induced programming of offspring thyroid gene expression through epigenetic mechanisms. Results: Maternal MID exposure led to increased gene and protein expression of thyrotropin-releasing hormone (TRH) and thyroid-stimulating hormone (TSH) in the hypothalamus and pituitary of the offspring animals. Thyroid protein and gene expression of sodium iodide symporter (NIS), TSH receptor (TSHR), thyroid peroxidase (TPO), thyroglobulin (TG), paired box 8 (PAX8), NK2 homeobox 1 (NKX2.1), and monocarboxylate transporter 8 (MCT8) were elevated in the offspring of MID-exposed animals. Epigenetic mechanisms appeared to contribute to the augmented thyroid gene expression in MID-exposed animals, with decreased DNA methyltransferase expression and reduced thyroid DNA global methylation. Additionally, histone 3 hypomethylation and increased acetylation of histones 3 and 4 were observed. Conclusion: The study suggests that MID exposure during pregnancy can be as harmful as severe iodine deficiency in programming the hypothalamus-pituitary-thyroid (HPT) axis, leading to HPT dysfunction during adult life. Consequently, our data suggest that monitoring iodine intake throughout pregnancy is crucial to prevent the occurrence of thyroid disorders in offspring during adulthood. Presentation: 6/1/2024

Deficiency of SLC26A3 promotes jejunal barrier damage in metabolic disease-susceptible transgenic pigs

Intestinal disorders are common in metabolic syndrome. However, their pathogenesis is still not fully understood. Pig and human intestines are highly similar in terms of associated metabolic processes. Here, we successfully constructed a metabolic disease-susceptible transgenic (TG) Bama pig model by knocking in three humanized disease risk genes with the CRISPR/Cas9 technique to assess its potential as a model for human intestinal diseases and explore the possible pathological mechanisms involved. We found that jejunal barrier integrity was disrupted and that the infiltration of inflammatory cells increased in TG pigs after high-fat and high-sucrose diet (HFHSD) treatment. We revealed significant differences in the transcriptome, associated microbiome profiles and microbial metabolite short-chain fatty acid (SCFA) content of the jejunum of TG pigs. Notably, we found that SLC26A3 was significantly downregulated in TG pigs. Knockdown or overexpression of the SLC26A3 gene in IPEC-J2 cells significantly affected the expression of MUC2, MUC13 and occludin. Furthermore, in vitro experiments further verified that CDX2 directly regulated the expression of SLC26A3. Mechanistically, CDX2 mediated intestinal barrier function by enhancing the expression of SLC26A3 by binding to its promoter region between −1120 and − 1070 bp. TG pigs represent a promising model that provides new insights into preclinical research on human intestinal metabolic diseases associated with metabolic disorders and revealed that SLC26A3 may be a potential therapeutic target for intestinal metabolic diseases.

Effect of Bovine Lactoferrin Treatment on Iron Homeostasis and Gene Expression Changes in Multiple Organ Dysfunctions During Wound Healing Process in Rats.

Injury systemically disrupts the homeostatic balance and can cause organ failure. LF mediates both iron-dependent and iron-independent mechanisms, and the role of LF in regulating iron homeostasis is vital in terms of metabolism. In this study, we evaluated the organ-level effect and gene expression change of bLf in the cutaneous repair process. An excisional full-thickness skin defect (FTSD) wound model was created in male Sprague Dawley rats (180-250 g) (n = 48) fed a high-fat diet (HFD) and the PHGPx, SLC7A11 and SLC40A1 genes and iron metabolism were evaluated. The animals were randomly divided into 6 groups: 1- Control, 2- bLf (200 mg/kg/day, oral), 3- FTSD (12 mm in diameter, dorsal), 4- HFD + bLf, 5- HFD + FTSD, 6- HFD + FTSD + bLf. Histologically, iron accumulation was demonstrated by Prussian blue staining in the liver, kidney, and intestinal tissues. Gene expression analysis was performed with qPCR. Histologically, iron accumulation was demonstrated by Prussian blue staining in the liver, kidney, and intestinal tissues. Prussian blue reactions were detected in the kidney. PHPGx and SLC7A11 genes in kidney and liver tissue were statistically significant (P < 0.05) except for the SLC40A1 gene (P > 0.05). Expression changes of the three genes were not statistically significant in analyses of rat intestinal tissue (P = 0.057). In the organ-level ferroptotic damage mechanism triggered by wound formation. BLf controls the expression of three genes and manages iron deposition in these three tissues. In addition, it suppressed the increase in iron that would drive the cell to ferroptosis and anemia caused by inflammation, thereby eliminating iron deposition in the tissues.

Generation of human induced pluripotent stem cell lines derived from two glucose transporter 1 deficiency syndrome patients

Glucose transporter 1 deficiency syndrome (GLUT1DS), caused by impaired glucose transport at the blood–brain barriers, leads to various central nervous system dysfunctions. A comprehensive understanding of the underlying disease pathogenesis is still lacking. In this study, we have generated GLUT1DS-specific human induced pluripotent stem cells (hiPSCs) derived from two patients. These established GLUT1DS-specific hiPSC lines showed self-renewal and pluripotency and carried heterozygous frameshift or missense mutations in the responsible SLC2A1 gene. These novel cell resources provide new avenues for understanding disease mechanisms and developing new therapies for GLUT1DS

The Pivotal Function of SLC16A1 and SLC16A1-AS1 in Cancer Progress: Molecular Pathogenesis and Prognosis.

More than 300 membranes make up the SLC family of transporters, utilizing an ion gradient or electrochemical potential difference to move their substrates across biological membranes. The SLC16 gene family contains fourteen members. Proton-linked transportation of monocarboxylates can be promoted by the transporters MCT1, which the SLC16A1 gene family encodes. Glycolysis is constitutively up-regulated in cancer cells, and the amount of lactate produced as a result is correlated with prognosis. Further speaking, SLC16A1 plays an essential role in controlling the growth and spread of tumors, according to mounting evidence. Additionally, LncRNAs are the collective term for all genes that produce RNA transcripts longer than 200 nucleotides but do not convert into proteins. It has steadily developed into a hub for research, offering an innovative approach to tumor study as technology related to molecular biology advances. The growing study has uncovered SLC16A1-AS1, an RNA that acts as an antisense to SLC16A1, which is erroneously expressed in various types of cancers. Therefore, we compiled the most recent information on the physiological functions and underlying processes of SLC16A1 and the LncRNA SLC16A1-AS1 during tumor development to explore their impact on cancer treatment and prognosis. We compiled the most recent information on the physiological functions and underlying processes of SLC16A1 and the LncRNA SLC16A1-AS1 during tumor development to explore their impact on cancer treatment and prognosis. Relevant studies were retrieved and collected through the PubMed system. After determining SLC16A1 and SLC16A1-AS1 as the research object, we found a close relationship between SLC16A1 and tumorigenesis as well as the influencing factors through the analysis of the research articles. SLC16A1 regulates lactate chemotaxis while uncovering SLC16A1- AS1 as an antisense RNA acting through multiple pathways; they affect the metabolism of tumor cells and have an impact on the prognosis of patients with various cancers.

Novel Homozygous Variant in the SLC19A2 Gene Causing Thiamine Responsive Megaloblastic Anemia Syndrome: A Disease to Be Considered in Diabetes Clinics

Novel Homozygous Variant in the SLC19A2 Gene Causing Thiamine Responsive Megaloblastic Anemia Syndrome: A Disease to Be Considered in Diabetes Clinics

Alveolar Microlithiasis in Clinical Practice: Case Report

Pulmonary alveolar microlithiasis is a rare disease characterized by the deposition of microliths in the alveoli due to mutations in the SLC34A2 gene. The diagnosis is made more frequently between the second and fourth decade of life incidentally in chest images, it has a progressive course, with clinicalradiological dissociation, with no known effective treatment except for lung transplantation.

Validating the splicing effect of rare variants in the SLC26A4 gene using minigene assay

BackgroundThe SLC26A4 gene is the second most common cause of hereditary hearing loss in human. The aim of this study was to utilize the minigene assay in order to identify pathogenic variants of SLC26A4 associated with enlarged vestibular aqueduct (EVA) and hearing loss (HL) in two patients.MethodsThe patients were subjected to multiplex PCR amplification and next-generation sequencing of common deafness genes (including GJB2, SLC26A4, and MT-RNR1), then bioinformatics analysis was performed on the sequencing data to identify candidate pathogenic variants. Minigene experiments were conducted to determine the potential impact of the variants on splicing.ResultsGenetic testing revealed that the first patient carried compound heterozygous variants c.[1149 + 1G > A]; [919–2 A > G] in the SLC26A4 gene, while the second patient carried compound heterozygous variants c.[2089 + 3 A > T]; [919–2 A > G] in the same gene. Minigene experiments demonstrated that both c.1149 + 1G > A and c.2089 + 3 A > T affected mRNA splicing. According to the ACMG guidelines and the recommendations of the ClinGen Hearing Loss Expert Panel for ACMG variant interpretation, these variants were classified as “likely pathogenic”.ConclusionsThis study identified the molecular etiology of hearing loss in two patients with EVA and elucidated the impact of rare variants on splicing, thus contributing to the mutational spectrum of pathogenic variants in the SLC26A4 gene.

Impaired hippocampal plasticity associated with loss of recycling endosomal SLC9A6/NHE6 is ameliorated by the TrkB agonist 7,8-dihydroxyflavone

Proper maintenance of intracellular vesicular pH is essential for cargo trafficking during synaptic function and plasticity. Mutations in the SLC9A6 gene encoding the recycling endosomal pH regulator (Na+, K+)/H+ exchanger isoform 6 (NHE6) are causal for Christianson syndrome (CS), a severe form of X-linked intellectual disability. NHE6 expression is also downregulated in other neurodevelopmental and neurodegenerative disorders, such as autism spectrum disorder and Alzheimer's disease, suggesting its dysfunction could contribute more broadly to the pathophysiology of other neurological conditions. To understand how ablation of NHE6 function leads to severe learning impairments, we assessed synaptic structure, function, and cellular mechanisms of learning in a novel line of Nhe6 knockout (KO) mice expressing a plasma membrane-tethered green fluorescent protein within hippocampal neurons. We uncovered significant reductions in dendritic spines density, AMPA receptor (AMPAR) expression, and AMPAR-mediated neurotransmission in CA1 pyramidal neurons. The neurons also failed to undergo functional and structural enhancement during long-term potentiation (LTP). Significantly, the selective TrkB agonist 7,8-dihydroxyflavone restored spine density as well as functional and structural LTP in KO neurons. TrkB activation thus may act as a potential clinical intervention to ameliorate cognitive deficits in CS and other neurodegenerative disorders.

A Highly Selective Fluorescent Probe for Monitoring the Thyroid Hormone Transporter Activity in Mammalian Cells.

Monocarboxylate transporter 8 (MCT8) is a trans-membrane transporter, which mediates the cellular delivery of thyroid hormones, L-thyroxine (T4) and 3,5,3'-triiodo-L-thyronine (T3). In humans, the MCT8 protein is encoded by the SLC16A2 gene and mutations in the transporter cause a genetic neurological disorder known as Allan-Herndon-Dudley Syndrome (AHDS). MCT8 deficiency leads to impaired transport of thyroid hormones in the brain. Radiolabelled T4 and T3 or LC/MS-MS methods have been used to monitor the thyroid hormone uptake through MCT8. Herein, we developed a fluorescent based assay to monitor the thyroid hormone uptake through MCT8. A dansyl-based fluorescent probe having L-thyroxine moiety is found to be highly selective towards MCT8 in living cells. The high selectivity of the probe towards MCT8 can be attributed to the halogen bond-mediated recognition by the transporter protein. The presence of a free carboxylic acid group is essential for the specificity of the probe towards MCT8. Additionally, the selectivity of the probe for MCT8 is abolished upon esterification of the carboxylic group. Similarly, MCT8 does not recognize the probe when it contains a free amine group.

New Transcriptomic Biomarkers for Detection of the Recombinant Human Erythropoietin (rHuEPO) MirCERA in Horses.

Detection and monitoring of biomarkers related to doping is particularly suitable for the development of analytical strategies dedicated to indirect detection of banned substances. Previous studies in horses have already allowed the investigation of transcriptomic biomarkers in equine blood associated with reGH and rHuEPO administrations. Our most recent developments continue to focus on the discovery and monitoring of transcriptomic biomarkers for the control of ESAs, and a collaborative study with WADA-accredited doping control laboratories has recently been initiated to conduct a pilot study. In humans, three mRNAs (ALAS2, CA1, and SLC4A1) were previously observed to be differentially expressed after blood doping and were associated with immature red blood cells, the so-called circulating reticulocytes. In horses, circulating reticulocytes are rarely observed even after rHuEPO administration. With the improved primers that detect the equine orthologues of the human mRNAs from the ALAS2, CA1, and SLC4A1 genes, we can now report the first evidence of the detection of the three biomarkers in equine blood. In addition, an upregulation of the mRNA levels of the three genes was observed after analysis of blood samples collected from MirCERA-treated animals, with kinetics similar to those previously documented in humans. Our data suggest that ALAS2 and CA1 are promising indirect biomarkers for the detection of recombinant EPO abuse in horses, as observed in humans.