PiT2 is an inorganic phosphate (Pi) transporter whose mutations are linked to primary familial brain calcification (PFBC). PiT2 mainly consists of two ProDom (PD) domains and a large intracellular loop region (loop7). The PD domains are crucial for the Pi transport, but the role of PiT2-loop7 remains unclear. In PFBC patients, mutations in PiT2-loop7 are mainly nonsense or frameshift mutations that probably cause PFBC due to C-PD1131 deletion. To date, six missense mutations have been identified in PiT2-loop7; however, the mechanisms by which these mutations cause PFBC are poorly understood. Here, we found that the p.T390A and p.S434W mutations in PiT2-loop7 decreased the Pi transport activity and cell surface levels of PiT2. Furthermore, we showed that these two mutations attenuated its membrane localization by affecting adenosine monophosphate-activated protein kinase (AMPK)- or protein kinase B (AKT)-mediated PiT2 phosphorylation. In contrast, the p.S121C and p.S601W mutations in the PD domains did not affect PiT2 phosphorylation but rather impaired its substrate-binding abilities. These results suggested that missense mutations in PiT2-loop7 can cause Pi dyshomeostasis by affecting the phosphorylation-regulated cell-surface localization of PiT2. This study helps understand the pathogenesis of PFBC caused by PiT2-loop7 missense mutations and indicates that increasing the phosphorylation levels of PiT2-loop7 could be a promising strategy for developing PFBC therapies.
Humans ; Cell Membrane ; Mutation, Missense ; Phosphates/metabolism* ; Sodium-Phosphate Cotransporter Proteins, Type III/genetics*

Idiopathic infantile hypercalcemia is characterized by hypercalcemia, dehydration, vomiting, and failure to thrive, and it is due to mutations in 24-hydroxylase (CYP24A1). Recently, mutations in sodium-phosphate cotransporter (SLC34A1) expressed in the kidney were discovered as an additional cause of idiopathic infantile hypercalcemia. This report describes a female infant admitted for evaluation of nephrocalcinosis. She presented with hypercalcemia, hypercalciuria, low intact parathyroid hormone level, and high 1,25-dihydroxyvitamin D3 level. Exome sequencing identified novel compound heterozygous mutations in SLC34A1 (c.1337G>A, c.1483C>T). The patient was treated with fluids for hydration, furosemide, a corticosteroid, and restriction of calcium/vitamin D intake. At the age of 7 months, the patient's calcium level was within the normal range, and hypercalciuria waxed and waned. Renal echogenicity improved on the follow-up ultrasonogram, and developmental delay was not noted. In cases of hypercalcemia with subsequent hypercalciuria, DNA analysis for SLC34A1 gene mutations and CYP24A1 gene mutations should be performed. Further studies are required to obtain long-term data on hypercalciuria and nephrocalcinosis.
Calcitriol ; Calcium ; Dehydration ; DNA ; Exome ; Failure to Thrive ; Female ; Follow-Up Studies ; Furosemide ; Humans ; Hypercalcemia ; Hypercalciuria ; Hypophosphatemia ; Infant ; Kidney ; Nephrocalcinosis ; Parathyroid Hormone ; Reference Values ; Sodium-Phosphate Cotransporter Proteins ; Ultrasonography ; Vitamin D ; Vitamin D3 24-Hydroxylase ; Vomiting

OBJECTIVES.: Sodium salicylate (SS) is well known for its ototoxic properties that induce functional and morphological changes in the cochlea and brain. Ginkgo biloba extract (GBE) has been widely used for treatment of various neurodegenerative diseases; however, its effects on salicylate-induced ototoxicity remain unclear. Herein, we examined the effects of EGb 761 (EGb), a standard form of GBE, on the plasticity of the N-methyl-D-aspartate receptor subunit 2B (GluN2B) in the inferior colliculus (IC) following SS administration. METHODS.: Seven-week-old Sprague Dawley rats (n=24) were randomly allocated to control, SS, EGb, and EGb+SS groups. The SS group received a single intraperitoneal SS injection (350 mg/kg), the EGb group received EGb orally for 5 consecutive days (40 mg/kg), and the EGb+SS group received EGb for 5 consecutive days, followed by an SS injection. The auditory brainstem responses (ABRs) were assessed at baseline and 2 hours after SS administration. GluN2B expression was examined by Western blot and immunohistochemistry. RESULTS.: There were no significant differences in ABR threshold shifts among the groups. The expression of the GluN2B protein normalized by which of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) was significantly lower in the EGb+SS group, as compared to the SS group (P=0.012). Weak and diffused GluN2B immunoreactivity was detected in the IC neural cells of the EGb+SS group, while those of the SS group exhibited strong and diffused GluN2B positivity. CONCLUSION.: EGb may play a role in regulating the GluN2B expression in the IC of salicylate-induced ototoxicity model.
Blotting, Western ; Brain ; Cochlea ; Evoked Potentials, Auditory, Brain Stem ; Ginkgo biloba ; Glyceraldehyde 3-Phosphate ; Immunohistochemistry ; Inferior Colliculi ; N-Methylaspartate ; Neurodegenerative Diseases ; Oxidoreductases ; Plastics ; Rats, Sprague-Dawley ; Sodium Salicylate

Proximal renal tubular acidosis (RTA) is caused by a defect in bicarbonate (HCO₃⁻) reabsorption in the kidney proximal convoluted tubule. It usually manifests as normal anion-gap metabolic acidosis due to HCO₃⁻ wastage. In a normal kidney, the thick ascending limb of Henle’s loop and more distal nephron segments reclaim all of the HCO₃⁻ not absorbed by the proximal tubule. Bicarbonate wastage seen in type II RTA indicates that the proximal tubular defect is severe enough to overwhelm the capacity for HCO₃⁻ reabsorption beyond the proximal tubule. Proximal RTA can occur as an isolated syndrome or with other impairments in proximal tubular functions under the spectrum of Fanconi syndrome. Fanconi syndrome, which is characterized by a defect in proximal tubular reabsorption of glucose, amino acids, uric acid, phosphate, and HCO₃⁻, can occur due to inherited or acquired causes. Primary inherited Fanconi syndrome is caused by a mutation in the sodium-phosphate cotransporter (NaPₐ-II) in the proximal tubule. Recent studies have identified new causes of Fanconi syndrome due to mutations in the EHHADH and the HNF4A genes. Fanconi syndrome can also be one of many manifestations of various inherited systemic diseases, such as cystinosis. Many of the acquired causes of Fanconi syndrome with or without proximal RTA are drug-induced, with the list of causative agents increasing as newer drugs are introduced for clinical use, mainly in the oncology field.
Acidosis ; Acidosis, Renal Tubular ; Amino Acids ; Cystinosis ; Extremities ; Fanconi Syndrome ; Glucose ; Kidney ; Nephrons ; Sodium-Phosphate Cotransporter Proteins ; Uric Acid

BackgroundIdiopathic basal ganglia calcification (IBGC) is a genetic disorder characterized by bilateral basal ganglia calcification and neural degeneration. In this study, we reported a new SLC2OA2 mutation of IBGC and reviewed relevant literature to explore the association between phenotypes and genotypes in Chinese IBGC patients.

MethodsClinical information of the proband and her relatives were collected comprehensively. Blood samples of both the patient and her father were obtained, and genetic screening related to IBGC was performed using second generation sequencing with their consent. Findings were confirmed by Sanger sequencing. Polyphen-2 was used to predict the potential association between mutations and disease. Then, we retrieved literatures of Chinese IBGC patients and explored the association between phenotype and genotype.

ResultsA novel mutation was identified through genetic testing, and it is suggested to be a damage mutation predicted by Polyphen-2. Through literature review, we found that SLC20A2 mutation is the most common cause for IBGC in China. Its hot spot regions are mainly on the 1 and 8 exons; the second common one is PDGFB where the hot spot covered a length of 220-230 bp localized on the 2 exon; moreover, Chinese IBGC patients featured early-onset, more severe movement disorder and relatively mild cognitive impairment compared with those in other countries.

ConclusionsThere is significant heterogeneity both in phenotype and genotype in Chinese IBGC patients. Further research of pathogenic mechanism of IBGC is required to eventually develop precise treatment for individuals who suffered this disease.

Asian Continental Ancestry Group ; Basal Ganglia Diseases ; genetics ; Calcinosis ; genetics ; Exons ; genetics ; Female ; Genetic Association Studies ; Humans ; Male ; Mutation ; genetics ; Neurodegenerative Diseases ; genetics ; Pedigree ; Phenotype ; Sodium-Phosphate Cotransporter Proteins, Type III ; genetics

The aim of this study was to compare fluoride release and surface changes according to different orthodontic bracket adhesives the application of fluoride products. We used non-fluoridated composite resin Transbond fluoridated composite resins Blugloo and LightBond, resin-modified glass ionomer Rely XTM Luting 2, and conventional glass ionomer Fuji I®. Fluoride release of five orthodontic bracket adhesives and fluoride release ability after application of three fluoride products (1.23% acidulated phosphate fluoride gel, Tooth Mousse Plus®, Fluor Protector, and a toothbrush with sodium fluoride-containing toothpaste) were measured using a fluoride electrode that was connected to an ion analyzer. After 4 weeks of fluoride application, the surface roughness and surface morphology were examined using a surface roughness tester and field emission scanning electron microscopy. The amounts of fluoride release were observed not only on application of Tooth Mousse Plus® and Fluor Protector on resin-modified glass ionomer Rely XTM Luting 2 and Fuji I®, but also during tooth brushing using fluoride-containing toothpaste. After application of Tooth Mousse Plus®, except Transbond XT, the surface roughness increased, and all orthodontic adhesives showed a partial drop of micro-particle filler. On application of 1.23% acidulated phosphate fluoride gel on all orthodontic bracket adhesives, their surface roughness increased. To bond the orthodontic bracket, resin-modified glass ionomer Rely XTM Luting 2 and Fuji I® adhesives are highly recommended if the amount of fluoride release is considered to confer a preventative effect on dental caries, and among the fluoride products, Tooth Mousse Plus® and Fluor Protector are better than 1.23% acidulated phosphate fluoride gel, and these are expected to prevent dental caries even during tooth brushing with fluoride-containing toothpaste.
Acidulated Phosphate Fluoride ; Adhesives* ; Composite Resins ; Dental Caries ; Dental Cements ; Electrodes ; Fluorides* ; Glass ; Microscopy, Electron, Scanning ; Orthodontic Brackets* ; Sodium ; Surface Properties* ; Tooth ; Toothpastes

OBJECTIVEThis study aimed to investigate the susceptibility of mice with streptozotocin(STZ)-induced diabetes mellitus (TIDM) to the uptake of pentavalent inorganic arsenic (iAsV) and the possible molecular mechanism.

METHODSTIDM was induced in mice by STZ. TIDM and normal mice were treated with 15.0 mg/kg Na2HAsO4·12H2O by intragastric administration. Then, the concentrations of arsenic in various tissues were measured by atomic fluorescence spectrometry. The gene expression levels of Pit1 and Pit2 were quantified by real-time RT-PCR, and their protein levels were detected by Western blotting in mouse heart, kidney, and liver tissues.

RESULTSThe concentrations of arsenic in STZ-induced TIDM mouse tissues were higher at 2 h after intragastric administration of Na2HAsO4·12H2O. Compared with the levels in normal mice, PIT1 and PIT2, which play a role in the uptake of iAsV, were upregulated in the livers and hearts of TIDM mice. PIT1 but not PIT2 was higher in TIDM mouse kidneys. The upregulation of Pit1 and Pit2 expression could be reversed by insulin treatment.

CONCLUSIONThe increased uptake of iAsV in TIDM mouse tissues may be associated with increased PIT1 and/or PIT2 expression.

Animals ; Arsenic ; pharmacokinetics ; Diabetes Mellitus, Experimental ; metabolism ; Environmental Pollutants ; pharmacokinetics ; Gene Expression Regulation ; physiology ; Male ; Mice ; Mice, Inbred ICR ; Sodium-Phosphate Cotransporter Proteins, Type III ; genetics ; metabolism ; Transcription Factor Pit-1 ; genetics ; metabolism

Basal Ganglia ; pathology ; Calcinosis ; complications ; Female ; Humans ; Middle Aged ; Mutation ; Sodium-Phosphate Cotransporter Proteins, Type III ; genetics ; Supranuclear Palsy, Progressive ; etiology

OBJECTIVETo investigate the correlation between polymorphisms of uric acid transporter related gene SLC17A1 and hyperuricemia (HUA) among ethnic Uygur patients from Xinjiang.

METHODSA case-control study was carried out, which enrolled 1036 patients with hyperuricemia and 1031 healthy controls. Two single nucleotide polymorphisms (SNPs) of the SLC17A1 gene were determined with Sequenom MassARRAY. Crossover analysis was used to assess the effect of interaction between above SNPs and alcohol drinking on uric acid level.

RESULTSGenotypic and allelic frequencies of the SLC17A1 gene at the two loci in the two groups were compared. The CT genotype of the rs9467596 locus and TC genotype of the rs2096386 locus showed a higher risk for hyperuricemia (OR=1.334, 95%CI:1.082-1.644; OR=1.242, 95%CI:1.015-1.519, respectively). Crossover analysis also revealed that the SLC17A1 rs2096386 polymorphism has a positive interaction with alcohol drinking in a multiplication model (ORint=1.21, P<0.05, OR>1).

CONCLUSIONSNP rs9467596 and rs2096386 of the SLC17A1 gene may have a correlation between hyperuricemia and alcohol drinking among Uygur patients.

Adult ; Aged ; Alcohol Drinking ; ethnology ; genetics ; Alleles ; Asian Continental Ancestry Group ; genetics ; China ; Ethnic Groups ; genetics ; Female ; Gene Frequency ; Genetic Predisposition to Disease ; ethnology ; genetics ; Genotype ; Humans ; Hyperuricemia ; ethnology ; genetics ; Male ; Middle Aged ; Odds Ratio ; Polymorphism, Single Nucleotide ; Risk Factors ; Sodium-Phosphate Cotransporter Proteins, Type I ; genetics ; Young Adult

OBJECTIVETo describe clinical and genetic feature in a Chinese family with familial idiopathic basal ganglia calcification 3 (IBGC-3) caused by a novel mutation in the SLC20A2 gene.

METHODSClinical data was collected from a family with familial IBGC-3. All of the family members underwent cerebral CT. Potential mutation of the SLC20A2 gene were screened in the proband, 5 symptomatic patients, 5 asymptomatic family members, and 100 healthy Chinese controls. Exon 8 of the SLC20A2 gene was cloned into plasmid and sequenced.

RESULTSThere were 6 symptomatic patients (3 males and 3 females) in an autosomal dominant pedigree. The patients manifested as juvenile-onset paroxysmal kinesigenic dyskinesia, in addition to pyramidal signs in proband. 5 patients alive had calcification in bilateral basal ganglia and subcortical areas. One asymptomatic member also had calcification in the brain; and 2 cases of asymptomatic young members had bilateral globus pallidus calcification. A novel c.1086delC mutation in SLC20A2 gene has been identified in proband and 7 family members with intracranial calcification. The deletion mutation was not found in 2 family members without intracranial calcification and healthy controls members. There is no clear relationship between clinical symptoms and the severity of calcification in cerebral CT.

CONCLUSIONFamilial idiopathic basal ganglia calcification caused by the SLC20A2 gene mutation can manifest as juvenile onset paroxysmal kinesigenic dyskinesia. Further study should be done to validate the unrelated relationships between the severity of calcification in IBGC 3 cranial CT and clinical symptoms.

Adolescent ; Adult ; Basal Ganglia Diseases ; genetics ; Calcinosis ; genetics ; Child ; Female ; Humans ; Male ; Mutation ; Neurodegenerative Diseases ; genetics ; Sodium-Phosphate Cotransporter Proteins, Type III ; genetics ; Tomography, X-Ray Computed