SPAK-knockout mice manifest Gitelman syndrome and impaired vasoconstriction.
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ABSTRACT:
SUBMITTER: Yang SS
PROVIDER: S-EPMC3014002 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Gitelman syndrome (GS), also referred to as familial hypokalemia-hypomagnesemia, is characterized by hypokalemic metabolic alkalosis in combination with significant hypomagnesemia and low urinary calcium excretion. The prevalence is estimated at approximately 1:40,000 and accordingly, the prevalence of heterozygotes is approximately 1% in Caucasian populations, making it one of the most frequent inherited renal tubular disorders. In the majority of cases, symptoms do not appear before the age of six years and the disease is usually diagnosed during adolescence or adulthood. Transient periods of muscle weakness and tetany, sometimes accompanied by abdominal pain, vomiting and fever are often seen in GS patients. Paresthesias, especially in the face, frequently occur. Remarkably, some patients are completely asymptomatic except for the appearance at adult age of chondrocalcinosis that causes swelling, local heat, and tenderness over the affected joints. Blood pressure is lower than that in the general population. Sudden cardiac arrest has been reported occasionally. In general, growth is normal but can be delayed in those GS patients with severe hypokalemia and hypomagnesemia.GS is transmitted as an autosomal recessive trait. Mutations in the solute carrier family12, member 3 gene, SLC12A3, which encodes the thiazide-sensitive NaCl cotransporter (NCC), are found in the majority of GS patients. At present, more than 140 different NCC mutations throughout the whole protein have been identified. In a small minority of GS patients, mutations in the CLCNKB gene, encoding the chloride channel ClC-Kb have been identified.Diagnosis is based on the clinical symptoms and biochemical abnormalities (hypokalemia, metabolic alkalosis, hypomagnesemia and hypocalciuria). Bartter syndrome (especially type III) is the most important genetic disorder to consider in the differential diagnosis of GS. Genetic counseling is important. Antenatal diagnosis for GS is technically feasible but not advised because of the good prognosis in the majority of patients.Most asymptomatic patients with GS remain untreated and undergo ambulatory monitoring, once a year, generally by nephrologists. Lifelong supplementation of magnesium (magnesium-oxide and magnesium-sulfate) is recommended. Cardiac work-up should be offered to screen for risk factors of cardiac arrhythmias. All GS patients are encouraged to maintain a high-sodium and high potassium diet. In general, the long-term prognosis of GS is excellent.
| S-EPMC2518128 | biostudies-literature
Project description:Angiopoietin-like protein (ANGPTL)8 (alternatively called TD26, RIFL, Lipasin, and Betatrophin) is a newly recognized ANGPTL family member that has been implicated in both triglyceride (TG) and glucose metabolism. Hepatic overexpression of ANGPTL8 causes hypertriglyceridemia and increased insulin secretion. Here we examined the effects of inactivating Angptl8 on TG and glucose metabolism in mice. Angptl8 knockout (Angptl8(-/-)) mice gained weight more slowly than wild-type littermates due to a selective reduction in adipose tissue accretion. Plasma levels of TGs of the Angptl8(-/-) mice were similar to wild-type animals in the fasted state but paradoxically decreased after refeeding. The lower TG levels were associated with both a reduction in very low density lipoprotein secretion and an increase in lipoprotein lipase (LPL) activity. Despite the increase in LPL activity, the uptake of very low density lipoprotein-TG is markedly reduced in adipose tissue but preserved in hearts of fed Angptl8(-/-) mice. Taken together, these data indicate that ANGPTL8 plays a key role in the metabolic transition between fasting and refeeding; it is required to direct fatty acids to adipose tissue for storage in the fed state. Finally, glucose and insulin tolerance testing revealed no alterations in glucose homeostasis in mice fed either a chow or high fat diet. Thus, although absence of ANGPTL8 profoundly disrupts TG metabolism, we found no evidence that it is required for maintenance of glucose homeostasis.
| S-EPMC3791734 | biostudies-literature
Project description:Ribonuclease, RNase A family, 9 (RNASE9) is a ribonuclease A superfamily member that is expressed only in the epididymis. It is a small, secreted polypeptide, it lacks ribonuclease activity, and its function(s) is unknown. However, epididymis-specific expression suggests a role in sperm maturation. We generated Rnase9(-/-) mice to study RNASE9 function in vivo. We confirm that RNASE9 expression is restricted to the epididymis. Within the epididymis, RNASE9 is first detected in midcaput, persists through the distal caput and corpus, and wanes in the cauda. Rnase9(-/-) mice are born at the expected Mendelian ratio, have normal postnatal growth and development, and have no outwardly apparent phenotype. Spermatogenesis is normal, and Rnase9-null sperm are morphologically normal. Rnase9(-/-) males have normal fertility in unrestricted mating trials, and fertilization rates in in vitro fertilization assays are indistinguishable from wild-type mice. Visual observations coupled with analyses of sperm velocities shortly after swim out from the corpus shows that motility of Rnase9-null sperm is significantly impaired. However, no differences between wild-type and Rnase9-null sperm are detected by computer-assisted sperm analysis 10-90 min after sperm isolation from the corpus or cauda. Assessment of capacitation-dependent signaling pathways in Rnase9-null sperm showed that, while levels of tyrosine phosphorylation of sperm proteins were normal, there was decreased phosphorylation of protein kinase A substrates upon capacitation compared to wild-type mice. In conclusion, RNASE9 is dispensable for fertility, but the absence of RNASE9 during epididymal transit results in impaired sperm maturation.
| S-EPMC4093998 | biostudies-literature
Project description:MAGEL2 is one of five protein-coding, maternally imprinted, paternally expressed genes in the Prader-Willi syndrome (PWS)-critical domain on chromosome 15q11-q13. Truncating pathogenic variants of MAGEL2 cause Schaaf-Yang syndrome (SHFYNG) (OMIM #615547), a neurodevelopmental disorder related to PWS. Affected individuals manifest a spectrum of neurocognitive and behavioral phenotypes, including intellectual disability and autism spectrum disorder (ASD). Magel2 knockout mice carrying a maternally inherited, imprinted wild-type (WT) allele and a paternally inherited Magel2-lacZ knock-in allele, which abolishes endogenous Magel2 gene function, exhibit several features reminiscent of the human Prader-Willi phenotypes, including neonatal growth retardation, excessive weight gain after weaning and increased adiposity in adulthood. They were shown to have altered circadian rhythm, reduced motor activity and reduced fertility. An extensive assessment for autism-like behaviors in this mouse model was warranted, because of the high prevalence of ASD in human patients. The behavior of Magel2 knockout mice and their WT littermates were assayed via open field, elevated plus maze, tube, three-chamber and partition tests. Our studies confirm decreased horizontal activity of male and female mice and increased vertical activity of females, in the open field. Both sexes spent more time in the open arm of the elevated plus maze, suggestive of reductions in anxiety. Both sexes displayed a lack of preference for social novelty, via a lack of discrimination between known and novel partners in the partition test. The in-depth investigation of behavioral profiles caused by Magel2 loss-of-function helps to elucidate the etiology of behavioral phenotypes both for SHFYNG and PWS in general.
| S-EPMC5495607 | biostudies-literature
Project description:BackgroundGitelman syndrome (GS) is an autosomal recessive salt-losing renal tubulopathy arising from mutations in the thiazide-sensitive Na-Cl cotransporter gene. Due to its low incidence and lack of awareness, GS can be easily misdiagnosed or missed in diagnosis.Case summaryA 24-year-old male presented with > 4 years of repeated limb weakness without any treatment. The previous day, the patient was bitten by ants and showed weakness of the lower limbs. The patient had hypokalemia (1.66-2.83 mmol/L), hypomagnesemia (0.4 mmol/L), hypocalciuria (1.51-2.46 mmol/d), metabolic alkalosis (7.47-7.54), normal blood pressure, and increased activity of aldosterone and plasma renin activity (PRA) (PRA 6.4 and 16.45 ng/mL/h and aldosterone 330.64 and 756.82 pg/mL in the supine and upright position, respectively). In addition, SLCI2A3 gene mutation with GS was diagnosed. Oral and intravenous supplementation with potassium and magnesium was initiated. Serum magnesium returned to 0.48 mmol/L and serum potassium returned to 3.08 mmol/L, alleviating the patient's fatigue symptoms.ConclusionGS should be considered in patients with hypokalemia complicated with hypomagnesemia. Genetic testing is essential to confirm the diagnosis.
| S-EPMC9258353 | biostudies-literature
Project description:BackgroundPathological angiogenesis contributes to various ocular, malignant, and inflammatory disorders, emphasizing the need to understand this process more precisely on a molecular level. Previously we found that CIB1, a 22 kDa regulatory protein, plays a critical role in endothelial cell function, angiogenic growth factor-mediated cellular functions, PAK1 activation, MMP-2 expression, and in vivo ischemia-induced angiogenesis. Since pathological angiogenesis is highly dependent on many of these same processes, we hypothesized that CIB1 may also regulate tumor-induced angiogenesis.MethodsTo test this hypothesis, we allografted either murine B16 melanoma or Lewis lung carcinoma cells into WT and CIB1-KO mice, and monitored tumor growth, morphology, histology, and intra-tumoral microvessel density.ResultsAllografted melanoma tumors that developed in CIB1-KO mice were smaller in volume, had a distinct necrotic appearance, and had significantly less intra-tumoral microvessel density. Similarly, allografted Lewis lung carcinoma tumors in CIB1-KO mice were smaller in volume and mass, and appeared to have decreased perfusion. Intra-tumoral hemorrhage, necrosis, and perivascular fibrosis were also increased in tumors that developed in CIB1-KO mice.ConclusionsThese findings suggest that, in addition to its other functions, CIB1 plays a critical role in facilitating tumor growth and tumor-induced angiogenesis.
| S-EPMC2941741 | biostudies-literature
Project description:Gitelman's syndrome (GS) is a rare, autosomal recessive, salt-losing tubulopathy caused by mutations in the SLC12A3 gene, which encodes the thiazide-sensitive NaCl cotransporter (NCC). Because 18 to 40% of suspected GS patients carry only one SLC12A3 mutant allele, large genomic rearrangements may account for unidentified mutations. Here, we directly sequenced genomic DNA from a large cohort of 448 unrelated patients suspected of having GS. We found 172 distinct mutations, of which 100 were unreported previously. In 315 patients (70%), we identified two mutations; in 81 patients (18%), we identified one; and in 52 patients (12%), we did not detect a mutation. In 88 patients, we performed a search for large rearrangements by multiplex ligation-dependent probe amplification (MLPA) and found nine deletions and two duplications in 24 of the 51 heterozygous patients. A second technique confirmed each rearrangement. Based on the breakpoints of seven deletions, nonallelic homologous recombination by Alu sequences and nonhomologous end-joining probably favor these intragenic deletions. In summary, missense mutations account for approximately 59% of the mutations in Gitelman's syndrome, and there is a predisposition to large rearrangements (6% of our cases) caused by the presence of repeated sequences within the SLC12A3 gene.
| S-EPMC3065225 | biostudies-literature
Project description:GLUT4 in muscle and adipose tissue is important in maintaining glucose homeostasis. However, the role of insulin-responsive GLUT4 in the central nervous system has not been well characterized. To assess its importance, a selective knockout of brain GLUT4 (BG4KO) was generated by crossing Nestin-Cre mice with GLUT4-floxed mice. BG4KO mice had a 99% reduction in GLUT4 protein expression throughout the brain. Despite normal feeding and fasting glycemia, BG4KO mice were glucose intolerant, demonstrated hepatic insulin resistance, and had reduced glucose uptake in the brain. In response to hypoglycemia, BG4KO mice had impaired glucose sensing, noted by impaired epinephrine and glucagon responses and impaired c-fos activation in the hypothalamic paraventricular nucleus. Moreover, in vitro glucose sensing of glucose-inhibitory neurons from the ventromedial hypothalamus was impaired in BG4KO mice. In summary, BG4KO mice are glucose intolerant, insulin resistant, and have impaired glucose sensing, indicating a critical role for brain GLUT4 in sensing and responding to changes in blood glucose.
| S-EPMC5319720 | biostudies-literature
Project description:The Id3 gene has been shown to play important roles in the development and function of broad tissue types including B and T cells. Id3 deficient mice develop autoimmune disease similar to human Sjögren's syndrome. Both B and T lymphocytes have been implicated to contribute to the disease phenotype in this disease model. In order to gain a better understanding of individual cell types in this disease model, we generated an Id3 conditional allele. An LckCre transgene was used to induce Id3 deletion in developing T cells. We showed that the Id3 gene was efficiently disrupted in early thymocyte development prior to T cell receptor (TCR)-mediated positive selection. Consequently, thymocyte maturation was impaired in the conditional knockout mice. These mice developed exocrinopathy starting at two months of age and subsequently exhibited high incidence of lymphocyte infiltration to salivary glands between eight and 12 months of age. This progressive feature of disease development is very similar to those observed in Id3 germline knockout mice. This study establishes a new model for investigating the relationship between T cell development and autoimmune disease. Our observation provides an experimental case that autoimmune disease may be induced by acquired mutation in developing T cells.
| S-EPMC3025308 | biostudies-other
Project description:It has long been recognized that olfaction and emotion are linked. While chemosensory research using both human and rodent models have indicated a change in emotion can contribute to olfactory dysfunction, there are few studies addressing the contribution of olfaction to a modulation in emotion. In mice, olfactory deficits have been linked with heightened anxiety levels, suggesting that there could be an inverse relationship between olfaction and anxiety. Furthermore, increased anxiety is often co-morbid with psychiatric conditions such as attention disorders. Our study aimed to investigate the roles of olfaction in modulating anxiety. Voltage-gated potassium ion channel Kv1.3 knockout mice (Kv1.3-/-), which have heightened olfaction, and wild-type (WT) mice were examined for anxiety-like behaviors using marble burying (MB), light-dark box (LDB) and elevated-plus maze (EPM) tests. Because Kv1.3-/- mice have increased locomotor activity, inattentive and hyperactive behaviors were quantified for both genotypes. Kv1.3-/- mice showed increased anxiety levels compared to their WT counterparts and administration of methylphenidate (MPH) via oral gavage alleviated their increased anxiety. Object-based attention testing indicated young and older Kv1.3-/- mice had attention deficits and treatment with MPH also ameliorated this condition. Locomotor testing through use of a metabolic chamber indicated that Kv1.3-/- mice were not significantly hyperactive and MPH treatment failed to modify this activity. Our data suggest that heightened olfaction does not necessarily lead to decreased anxiety levels, and that Kv1.3-/- mice may have behaviors associated with inattentiveness.
| S-EPMC5867313 | biostudies-literature