A novel SLC6A8 mutation associated with intellectual disabilities in a Chinese family exhibiting creatine transporter deficiency: case report

Wang, Qin; Yang, Jinghong; Liu, Yang; Li, Xingping; Luo, Fuwei; Xie, Jiansheng

doi:10.1186/s12881-018-0707-5

Cited by 15 publications

(7 citation statements)

References 32 publications

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“…Rasd2 and Igfbp5 were identified by a recent study as candidate genes associated with epileptogenicity in KA model of TLE 49 and Fxyd7 to be altered after seizure preconditioning using pilocarpine model 50 . Human studies reported Cdkn1a to be upregulated in patients with epilepsy 51 and deficiency in Slc6a8 was reported to result in intractable epilepsy and cognitive impairment 52 . Although, with the given dataset, we are not able to deduce any direct involvement in seizure modulation, many of those genes were previously described to be associated with neuronal excitability, seizures or epilepsy.…”

Section: Changes In the Expression Of Par Bzip Transcription Factors mentioning

confidence: 99%

Aberrant expression of PAR bZIP transcription factors is associated with epileptogenesis, focus on hepatic leukemia factor

Rambousek

Gschwind

Lafourcade

et al. 2020

Sci Rep

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epilepsy is a widespread neurological disease characterized by abnormal neuronal activity resulting in recurrent seizures. there is mounting evidence that a circadian system disruption, involving clock genes and their downstream transcriptional regulators, is associated with epilepsy. in this study, we characterized the hippocampal expression of clock genes and pAR bZip transcription factors (tfs) in a mouse model of temporal lobe epilepsy induced by intrahippocampal injection of kainic acid (KA). the expression of PAR bZIP TFs was significantly altered following KA injection as well as in other rodent models of acquired epilepsy. Although the PAR bZIP TFs are regulated by proinflammatory cytokines in peripheral tissues, we discovered that the regulation of their expression is inflammation-independent in hippocampal tissue and rather mediated by clock genes and hyperexcitability. furthermore, we report that hepatic leukemia factor (Hlf), a member of pAR bZip tfs family, is invariably downregulated in animal models of acquired epilepsy, regulates neuronal activity in vitro and its overexpression in dentate gyrus neurons in vivo leads to altered expression of genes associated with seizures and epilepsy. overall, our study provides further evidence of pAR bZip tfs involvement in epileptogenesis and points to Hlf as the key player. Epilepsy is a chronic brain disease characterized by the occurrence of recurrent seizures, which are the result of an excessive electrical discharge or hypersynchronization of a group of neurons in distinct areas of the brain. Temporal lobe epilepsy (TLE) is the most common subtype of acquired epilepsy 1. TLE, affecting the hippocampal formation and surrounding cortices of the temporal lobe, is associated with pathological changes including neuroinflammation and neurodegeneration resulting in impaired cognition 2. Recent studies provided converging evidence that the circadian system might be disrupted in epilepsy 3,4. At the molecular level, core clock genes form a transcriptional-translational feedback loop that drives their diurnal oscillations. The positive loop members CLOCK (or NPAS2) and BMAL1 form heterodimers that activate the expression of negative feedback loop members, CRY and PER, by binding to E-box motives in their promoters. CRY and PER consequently inhibit the transcriptional activity of CLOCK/NPAS2:BMAL1 complex and thereby their own expression. The inhibition of BMAL1 expression is additionally mediated in a second negative feedback loop by REV-erb-α and RORC 5,6. Moreover, core clock components interact with the expression of the proline and acidic amino acid-rich basic leucine zipper (PAR bZIP) transcription factors (TFs). This family is composed of three activators, DBP (albumin D-site-binding protein), HLF (hepatic leukemia factor), TEF (thyrotrophic embryonic factor) and one suppressor of transcription E4 Promoter-Binding Protein 4 (E4BP4), known also as NFIL3 7-10. It has been shown that E4BP4 has an opposite rhythm of oscillation compared to positive members of PAR...

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Section: Changes In the Expression Of Par Bzip Transcription Factors mentioning

confidence: 99%

Aberrant expression of PAR bZIP transcription factors is associated with epileptogenesis, focus on hepatic leukemia factor

Rambousek

Gschwind

Lafourcade

et al. 2020

Sci Rep

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“…The chorionic villus was sampled from the third fetus at 14 weeks of pregnancy. DNA was extracted as previously described [19]. The first fetus was not available for molecular testing.…”

Section: Methodsmentioning

confidence: 99%

Compound heterozygous variants in MYH11 underlie autosomal recessive megacystis-microcolon-intestinal hypoperistalsis syndrome in a Chinese family

et al. 2019

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Megacystis-microcolon-intestinal-hypoperistalsis syndrome (MMIHS) is a rare and severe disorder characterized by functional obstruction in the urinary and gastrointestinal tract. The molecular basis of this condition has been defined recently. Heterozygous variants in ACTG2, homozygous mutations in LMOD1, MYLK, and MYH9 were related to the pathogenesis of the syndrome, which encodes proteins involved in the process of smooth muscle contraction, supporting a myopathic basis for the disease. Recent studies have identified homozygous or compound heterozygous variants in MYH11 as a candidate gene of MMIHS. In this report, we described a nonconsanguineous Chinese family with three male fetuses affected with megacystis. Trio-targeted exome sequencing identified compound heterozygous variants, c.2051 G > A (p.R684H) and c.3540_3541delinsTT (p.(E1180D, Q1181Ter)), in MYH11 (NM_001040114). The variants were inherited from the parents, respectively. Western blotting showed a marked decrease in MYH11 protein in the proband’s umbilical cord tissue compared with the control sample. The study’s results confirmed that MYH11 is a candidate gene for MMIHS with autosomal recessive (AR) inheritance and expanded the mutation spectrum for this clinical condition. Combining clinical phenotype with molecular diagnosis may enable the identification of candidate genes for potential monogenic diseases and facilitate accurate genetic counseling, informed decision-making, and prenatal diagnosis.

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“…Finally, it is worth noting that congenital CRT deficiency is associated with autism, epilepsy, neurological defects, and intellectual disabilities [276,277]. This neurometabolic disorder is part of the Cr deficiency syndrome [52].…”

Section: What Is the Basis Of Creatine Transport?mentioning

confidence: 99%

Metabolic Basis of Creatine in Health and Disease: A Bioinformatics-Assisted Review

et al. 2021

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Creatine (Cr) is a ubiquitous molecule that is synthesized mainly in the liver, kidneys, and pancreas. Most of the Cr pool is found in tissues with high-energy demands. Cr enters target cells through a specific symporter called Na+/Cl−-dependent Cr transporter (CRT). Once within cells, creatine kinase (CK) catalyzes the reversible transphosphorylation reaction between [Mg2+:ATP4−]2− and Cr to produce phosphocreatine (PCr) and [Mg2+:ADP3−]−. We aimed to perform a comprehensive and bioinformatics-assisted review of the most recent research findings regarding Cr metabolism. Specifically, several public databases, repositories, and bioinformatics tools were utilized for this endeavor. Topics of biological complexity ranging from structural biology to cellular dynamics were addressed herein. In this sense, we sought to address certain pre-specified questions including: (i) What happens when creatine is transported into cells? (ii) How is the CK/PCr system involved in cellular bioenergetics? (iii) How is the CK/PCr system compartmentalized throughout the cell? (iv) What is the role of creatine amongst different tissues? and (v) What is the basis of creatine transport? Under the cellular allostasis paradigm, the CK/PCr system is physiologically essential for life (cell survival, growth, proliferation, differentiation, and migration/motility) by providing an evolutionary advantage for rapid, local, and temporal support of energy- and mechanical-dependent processes. Thus, we suggest the CK/PCr system acts as a dynamic biosensor based on chemo-mechanical energy transduction, which might explain why dysregulation in Cr metabolism contributes to a wide range of diseases besides the mitigating effect that Cr supplementation may have in some of these disease states.

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A novel SLC6A8 mutation associated with intellectual disabilities in a Chinese family exhibiting creatine transporter deficiency: case report

Cited by 15 publications

References 32 publications

Aberrant expression of PAR bZIP transcription factors is associated with epileptogenesis, focus on hepatic leukemia factor

Aberrant expression of PAR bZIP transcription factors is associated with epileptogenesis, focus on hepatic leukemia factor

Compound heterozygous variants in MYH11 underlie autosomal recessive megacystis-microcolon-intestinal hypoperistalsis syndrome in a Chinese family

Metabolic Basis of Creatine in Health and Disease: A Bioinformatics-Assisted Review

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