In pancreatic acinar cells Ca(2+)-dependent secretagogues promote the fusion of zymogen granules (ZG) with the apical plasma membrane (PM) and exocytosis of digestive enzymes. In addition to exocytotic fusion complexes between SNARE proteins in the ZG membrane (ZGM) and the apical PM, enzyme secretion elicited by Ca(2+)-dependent secretagogues requires cytosolic Cl and K+ and is inhibited by blockers of Cl- and K+-channels. We have identified a Cl-conductance activated by ATP, and a K+-conductance (with properties similar to ATP-sensitive K+-channels), regulated by the granule matrix protein Zg-16p in the ZGM. Both conductances are inversely regulated by a 65-kD mdr1 gene product. We have also identified a novel Ca(2+)-activated anion conductance in ZGM, the Ca(2+)-sensitivity of which increases 50-fold when Cl is replaced by 1. This conductance is blocked by micromolar H2-DIDS or DTT, reminiscent of a family of epithelial Ca(2+)-activated Cl -channels (CaCC). Expression of a CaCC in exocrine pancreas has been confirmed by RT-PCR analysis, and by immunoblotting and immunogold labeling of ZG membranes. These data suggest that ion channels in the ZGM are essential elements in pancreatic exocytosis.
Animal ; Chloride Channels/metabolism* ; Chloride Channels/genetics ; Exocytosis/physiology* ; Gene Expression/physiology ; P-Glycoprotein/metabolism ; P-Glycoprotein/genetics ; Pancreas/secretion* ; Pancreas/cytology ; Potassium Channels/metabolism* ; Potassium Channels/genetics ; Secretory Vesicles/secretion ; Secretory Vesicles/metabolism* ; Support, U.S. Gov't, P.H.S.

OBJECTIVETo investigate chloride channel 1 (CLCN1) gene mutation and clinical features of 2 Chinese patients with myotonia congenita.

METHODSClinical data of a patient from a family affected with myotonia congenita in addition with a sporadic patient from Fujian province were analyzed. Exons of CLCN1 gene were amplified and sequenced.

RESULTSThe proband from the affected family was found to carry a c.1024G>A heterozygous missense mutation in exon 8, whilst the sporadic patient has carried a c.1292C>T heterozygous missense mutation in exon 11.

CONCLUSIONDetection of CLCN1 gene mutation is an effective method for the diagnosis of myotonia congenita. Exon 8 of CLCN1 gene may be a mutational hotspot in Chinese patients with myotonia congenita.

Adolescent ; Base Sequence ; Chloride Channels ; genetics ; Exons ; Heterozygote ; Humans ; Male ; Mutation ; Myotonia Congenita ; diagnosis ; genetics ; Pedigree

Asian Continental Ancestry Group ; Bartter Syndrome ; genetics ; Child ; Chloride Channels ; genetics ; Humans ; Male ; Mutation

INTRODUCTIONIn this paper, we report a novel VMD2 gene mutation in a Chinese family with Best vitelliform macular dystrophy.

MATERIALS AND METHODSOphthalmologic examination and optical coherence tomography (OCT) were performed in 2 members of this family. Mutational screening was performed by single-strand conformation polymorphism (SSCP) and direct sequencing of PCR-amplified DNA fragments, corresponding to the 11 exons of the gene.

RESULTSSequence analysis identified a previously unreported C to G change, predicting a Phe-113-Leu substitution. Both the proband and his sister harboured this novel mutation. Each had bilateral vitelliform lesions.

CONCLUSIONSA novel mutation in the VMD2 gene (C427G) was found in Chinese patients with Best vitelliform macular dystrophy.

Adult ; Bestrophins ; China ; Chloride Channels ; Eye Proteins ; genetics ; Female ; Humans ; Macular Degeneration ; genetics ; Male ; Mutation ; Pedigree

Recently, more and more studies have discovered that some diseases result from gene defect and functional variation of ion channels, which are called ion passage diseases or ion channelopathies. Meanwhile, it has been found that even though many diseases do not fall into the category of the ion passage disease, some links or passages during the disease development are closely related with the malfunction of ion channels, and many drugs can prevent and cure these diseases by acting on ion channels. Therefore, the relationship between physiology/pathophysiology and ion channels is gradually becoming one of the hot topics in the current researches. The recent progress in the researches on the relationship between penile erection and ion channels is briefly reviewed in this article.
Calcium Channels ; physiology ; Chloride Channels ; physiology ; Connexin 43 ; genetics ; Erectile Dysfunction ; etiology ; Humans ; Ion Channels ; physiology ; Male ; Penile Erection ; physiology ; Potassium Channels ; physiology

OBJECTIVETo study the clinical features and gene mutations of 4 Chinese children with Dent disease.

METHODSThe clinical and laboratory data of 4 children with Dent disease were analyzed retrospectively. Genetic testing of the 4 cases was carried out.

RESULTSAll of 4 cases were boys. The first impression of Cases 1-3 was Fanconi syndrome. Proteinuria was presented as the first impression in Case 4. All 4 boys presented with low-molecular weight proteinuria (LMWP) and hypercalciuria, including 3 cases with hematuria, 1 case with kidney stones, 2 cases with nephrocalcinosis, 3 cases with hypophosphatemia, and 3 cases with rickets. Mutations of the CLCN5 gene were revealed in three patients (Cases 1, 2 and 4), including exon 6-7del, c.785_787de l(p.263del Leu) and c.1039 C>T (p.Arg347Term). The first two gene mutations had never reported before.

CONCLUSIONSUrine protein electrophoresis should be carried out for patients with proteinuria. Dent disease should be taken into consideration when patients with Fanconi syndrome have hypercalciuria, nephrocalcinosis or kindey stones. Genetic analyses are needed for a definite diagnosis.

Child ; Child, Preschool ; Chloride Channels ; genetics ; Dent Disease ; drug therapy ; genetics ; Humans ; Mutation ; Phosphoric Monoester Hydrolases ; genetics

OBJECTIVETo investigate the role of ClC-3 chloride channels in regulatory volume decrease (RVD) of nasopharyngeal carcinoma (NPC) CNE-2Z cells.?

METHODSClC-3 siRNA was transfected into CNE-2Z cells in the presence of the transfection reagent HiPerFect Reagent(TM). The transfection efficiency of ClC-3 siRNA was detected by flow cytometry. The expression of ClC-3 protein was detected by Western blotting, and the changes of cell volume in 160 mOsmol/L hypotonic solution were determined by image analysis.

RESULTSThe transfection efficiency of ClC-3 siRNA was (63.8∓3.8)% (n=3, P<0.01), and compared with the control group, ClC-3 siRNA transfection resulted in a reduction of ClC-3 expression by (60.9∓4.0)% (n=3, P<0.01). The hypotonic challege (160 mOsmol/L) caused cell swelling and induced RVD. In the control group, hypotonic solution bath for 35 min resulted in a RVD of (42.6∓2.8)% (n=20), which was significantly decreased to (10.5∓4.8)% (n=16) in ClC-3 siRNA-transfected cells, demonstrating a reduction of RVD capacity by 75.4% (P<0.01).?

CONCLUSIONThe capacity of RVD is significantly reduced in CNE-2Z cells by ClC-3 chloride channel protein knock-down via ClC-3 siRNA transfection, indicating an important role of ClC-3 chloride channels in the RVD of CNE-2Z cells.

Cell Line, Tumor ; Cell Size ; Chloride Channels ; genetics ; Humans ; Nasopharyngeal Neoplasms ; genetics ; pathology ; RNA Interference ; RNA, Small Interfering ; genetics ; Transfection

Bartter syndrome is an inherited metabolic disorder characterized by hypokalemic alkalosis and high rennin-angiotensin-aldosteronism which can occur at all ages but mainly in childhood. Classical Bartter syndrome is caused by loss-of-function variants in the gene encoding basolateral chloride channel ClC-Kb (CLCNKB), which is a common type of Bartter syndrome characterized with diverse clinical manifestations ranging from severe to very mild. This article reviews the function and mechanism of CLCNKB variants in Chinese population and the genotype-phenotype correlation of CLCNKB variants in classical Bartter syndrome.
Asian Continental Ancestry Group ; Bartter Syndrome ; genetics ; pathology ; Chloride Channels ; genetics ; Genetic Association Studies ; Humans ; Research ; trends

Objective: To investigate the clinical presentation and genetic characteristics of malignant infantile osteopetrosis. Methods: This was a retrospective case study. Thirty-seven children with malignant infantile osteopetrosis admitted into Beijing Children's Hospital from January 2013 to September 2022 were enrolled in this study. According to the gene mutations, the patients were divided into the CLCN7 group and the TCIRG1 group. Clinical characteristics, laboratory tests, and prognosis were compared between two groups. Wilcoxon test or Fisher exact test were used in inter-group comparison. The survival rate was estimated with the Kaplan-Meier method and the Log-Rank test was used to compare the difference in survival between groups. Results: Among the 37 cases, there were 22 males and 15 females. The age of diagnosis was 0.5 (0.2, 1.0) year. There were 13 patients (35%) and 24 patients (65%) with mutations in CLCN7 and TCIRGI gene respectively. Patients in the CLCN7 group had an older age of diagnosis than those in the TCIRGI group (1.2 (0.4, 3.6) vs. 0.4 (0.2, 0.6) years, Z=-2.60, P=0.008). The levels of serum phosphorus (1.7 (1.3, 1.8) vs. 1.1 (0.8, 1.6) mmol/L, Z=-2.59, P=0.010), creatine kinase isoenzyme (CK-MB) (457 (143, 610) vs. 56 (37, 82) U/L, Z=-3.38, P=0.001) and the level of neutrophils (14.0 (9.9, 18.1) vs. 9.2 (6.7, 11.1) ×10⁹/L, Z=-2.07, P=0.039) at diagnosis were higher in the CLCN7 group than that in the TCIRG1 group. However, the level of D-dimer in the CLCN7 group was lower than that in the TCIRGI group (2.7 (1.0, 3.1) vs. 6.3 (2.5, 9.7) μg/L, Z=2.83, P=0.005). After hematopoietic stem cell transplantation, there was no significant difference in 5-year overall survival rate between the two groups (92.3%±7.4% vs. 83.3%±7.6%, χ²=0.56, P=0.456). Conclusions: TCIRGI gene mutations are more common in children with osteopetrosis. Children with TCIRGI gene mutations have younger age, lower levels of phosphorus, CK-MB, and neutrophils and higher level of D-dimer at the onset. After hematopoietic stem cell transplantation, patients with CLCN7 or TCIRGI gene mutations have similar prognosis.
Child ; Male ; Female ; Humans ; Osteopetrosis/therapy* ; Retrospective Studies ; Prognosis ; Genes, Recessive ; Phosphorus ; Chloride Channels/genetics* ; Vacuolar Proton-Translocating ATPases/genetics*

OBJECTIVE To explore the genetic mechanism for a family affected with cardiac conduction block. METHODS Affected family members were screened for potential mutations of known candidate genes. As no pathogenic mutation was found, two patients and one healthy member from the family were further analyzed by exomic sequencing followed by Sanger sequencing. The pathogenicity of suspected mutation was analyzed using bioinformatics software. RESULTS Sequencing of the full exome has identified a c.G1725T mutation in the CLCA2 gene. Sanger sequencing has detected the same mutation in all five patients, but not in the normal member from the family. Bioinformatics analysis indicated that the mutation has resulted in substitution of the 575th amino acid cysteine (C) by tryptophan (W). The site is highly conserved and becomes pathogenic with the mutation. CONCLUSION The heterozygous c.G1725T mutation in exon 11 of the CLCA2 gene probably underlies the disease and fit the autosomal dominant pattern of inheritance.
Amino Acid Sequence ; Chloride Channels ; genetics ; Computational Biology ; Female ; Heart Block ; genetics ; Humans ; Male ; Middle Aged ; Molecular Sequence Data ; Mutation