Hybridisation-based resequencing of 17 X-linked intellectual disability genes in 135 patients reveals novel mutations in ATRX, SLC6A8 and PQBP1

Jensen, Lars Riff; Chen, Wei; Moser, Bettina A.; Lipkowitz, Bettina; Schroeder, Christopher; Musante, Luciana; Tzschach, Andreas; Kalscheuer, Vera M.; Meloni, Ilaria; Raynaud, Martine; Esch, Hilde Van; Chelly, Jamel; Brouwer, Arjan Pm de; Hackett, Anna; Haar, Selma van der; Henn, Wolfram; Gécz, Jozef; Rieß, Olaf; Bonin, Michael; Reinhardt, Richard; Ropers, Hans‐Hilger; Kuß, Andreas W.

doi:10.1038/ejhg.2010.244

Cited by 23 publications

(19 citation statements)

References 16 publications

(19 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Slc6A8 is critically important for proper function of the brain, as genetic defects of Slc6A8 lead to mental retardation with seizures [63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80]. Slc6A8 deficient mice suffer from learning and memory deficits resembling human Slc6A8 deficiency [63].…”

Section: Discussionmentioning

confidence: 99%

Upregulation of the Creatine Transporter Slc6A8 by Klotho

Almilaji

Sopjani

Elvira

et al. 2014

Kidney Blood Press Res

View full text Add to dashboard Cite

Background/Aims: The transmembrane Klotho protein contributes to inhibition of 1,25(OH)₂D₃ formation. The extracellular domain of Klotho protein could function as an enzyme with e.g. β-glucuronidase activity, be cleaved off and be released into blood and cerebrospinal fluid. Klotho regulates several cellular transporters. Klotho protein deficiency accelerates the appearance of age related disorders including neurodegeneration and muscle wasting and eventually leads to premature death. The main site of Klotho protein expression is the kidney. Klotho protein is also appreciably expressed in other tissues including chorioid plexus. The present study explored the effect of Klotho protein on the creatine transporter CreaT (Slc6A8), which participates in the maintenance of neuronal function and survival. Methods: To this end cRNA encoding Slc6A8 was injected into Xenopus oocytes with and without additional injection of cRNA encoding Klotho protein. Creatine transporter CreaT (Slc6A8) activity was estimated from creatine induced current determined by two-electrode voltage-clamp. Results: Coexpression of Klotho protein significantly increased creatine-induced current in Slc6A8 expressing Xenopus oocytes. Coexpression of Klotho protein delayed the decline of creatine induced current following inhibition of carrier insertion into the cell membrane by brefeldin A (5 µM). The increase of creatine induced current by coexpression of Klotho protein in Slc6A8 expressing Xenopus oocytes was reversed by β-glucuronidase inhibitor (DSAL). Similarly, treatment of Slc6A8 expressing Xenopus oocytes with recombinant human alpha Klotho protein significantly increased creatine induced current. Conclusion: Klotho protein up-regulates the activity of creatine transporter CreaT (Slc6A8) by stabilizing the carrier protein in the cell membrane, an effect requiring β-glucuronidase activity of Klotho protein.

show abstract

Section: Discussionmentioning

confidence: 99%

Upregulation of the Creatine Transporter Slc6A8 by Klotho

Almilaji

Sopjani

Elvira

et al. 2014

Kidney Blood Press Res

View full text Add to dashboard Cite

show abstract

“…The carrier plays an important role in the regulation of neuronal function and neuroexcitability [39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56]. The WNK-SPAK/OSR1 kinase pathway is similarly involved in the regulation of neuronal excitation [27,74].…”

Section: Discussionmentioning

confidence: 99%

“…SLC6A8 is expressed in a wide variety of tissues, such as kidney, small intestine, heart, skeletal muscle, brain and retina [35,36,37,38]. Genetic disorders affecting SLC6A8 lead to mental retardation with seizures [39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56]. …”

Section: Introductionmentioning

confidence: 99%

Negative Regulation of the Creatine Transporter SLC6A8 by SPAK and OSR1

Fezai

Elvira

Borrás

et al. 2014

Kidney Blood Press Res

View full text Add to dashboard Cite

Background/Aims: Transport regulation involves several kinases including SPAK (SPS1-related proline/alanine-rich kinase) and OSR1 (oxidative stress-responsive kinase 1), which are under control of WNK (with-no-K[Lys]) kinases. The present study explored whether SPAK and/or OSR1 participate in the regulation of the creatine transporter CreaT (SLC6A8), which accomplishes Na⁺ coupled cellular uptake of creatine in several tissues including kidney, intestine, heart, skeletal muscle and brain. Methods: cRNA encoding SLC6A8 was injected into Xenopus laevis oocytes with or without additional injection of cRNA encoding wild-type SPAK, constitutively active ^T233ESPAK, WNK insensitive ^T233ASPAK, catalytically inactive ^D212ASPAK, wild-type OSR1, constitutively active ^T185EOSR1, WNK insensitive ^T185AOSR1 and catalytically inactive ^D164AOSR1. Transporter activity was determined from creatine (1 mM) induced current utilizing dual electrode voltage clamp. Results: Coexpression of wild-type SPAK and of ^T233ESPAK, but not of ^T233ASPAK or of ^D212ASPAK was followed by a significant decrease of creatine induced current in SLC6A8 expressing oocytes. Coexpression of SPAK significantly decreased maximal transport rate. Coexpression of wild-type OSR1, ^T185EOSR1 and ^T185AOSR1 but not of ^D164AOSR1 significantly negatively regulated SLC6A8 activity. OSR1 again decreased significantly maximal transport rate. Conclusions: Both, SPAK and OSR1, are negative regulators of the creatine transporter SLC6A8.

show abstract

“…Those carriers may similarly be candidates for regulation by TTBK2. Genetic defects affecting the creatine transporter CreaT result in mental retardation with seizures [65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82]. Defective cellular taurine uptake by TauT fosters apoptosis [83,84,85,86,87,88,89,90,91].…”

Section: Discussionmentioning

confidence: 99%

Upregulation of Na⁺,Cl^--Coupled Betaine/ γ-Amino-Butyric Acid Transporter BGT1 by Tau Tubulin Kinase 2

Almilaji

Muñoz

Hosseinzadeh

et al. 2013

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: The serine/threonine kinase Tau-tubulin-kinase 2 (TTBK2) is expressed in various tissues including kidney, liver and brain. Loss of function mutations of TTBK2 lead to autosomal dominant spinocerebellar ataxia type 11 (SCA11). Cell survival is fostered by cellular accumulation of organic osmolytes. Carriers accomplishing cellular accumulation of organic osmolytes include the Na⁺, Cl^--coupled betaine/γ-amino-butyric acid transporter BGT1. The present study explored whether TTBK2 participates in the regulation of BGT1 activity. Methods: Electrogenic transport of GABA was determined in Xenopus oocytes expressing BGT1 with or without wild-type TTBK2, truncated TTBK2[1-450] or kinase inactive mutants TTBK2- KD and TTBK2[1-450]-KD. Results: Coexpression of wild-type TTBK2, but not of TTBK2[1-450], TTBK2-KD or TTBK2[1-450]-KD, increased electrogenic GABA transport. Wildtype TTBK2 increased the maximal transport rate without significantly modifying affinity of the carrier. Coexpression of wild-type TTBK2 significantly delayed the decline of transport following inhibition of carrier insertion with brefeldin A, indicating that wild-type TTBK2 increased carrier stability in the cell membrane. Conclusion: Tau-tubulin-kinase 2 TTBK2 is a powerful stimulator of the osmolyte and GABA transporter BGT1.

show abstract

Hybridisation-based resequencing of 17 X-linked intellectual disability genes in 135 patients reveals novel mutations in ATRX, SLC6A8 and PQBP1

Cited by 23 publications

References 16 publications

Upregulation of the Creatine Transporter Slc6A8 by Klotho

Upregulation of the Creatine Transporter Slc6A8 by Klotho

Negative Regulation of the Creatine Transporter SLC6A8 by SPAK and OSR1

Upregulation of Na⁺,Cl^--Coupled Betaine/ γ-Amino-Butyric Acid Transporter BGT1 by Tau Tubulin Kinase 2

Contact Info

Product

Resources

About

Hybridisation-based resequencing of 17 X-linked intellectual disability genes in 135 patients reveals novel mutations in ATRX, SLC6A8 and PQBP1

Cited by 23 publications

References 16 publications

Upregulation of the Creatine Transporter Slc6A8 by Klotho

Upregulation of the Creatine Transporter Slc6A8 by Klotho

Negative Regulation of the Creatine Transporter SLC6A8 by SPAK and OSR1

Upregulation of Na+,Cl--Coupled Betaine/ γ-Amino-Butyric Acid Transporter BGT1 by Tau Tubulin Kinase 2

Contact Info

Product

Resources

About

Upregulation of Na⁺,Cl^--Coupled Betaine/ γ-Amino-Butyric Acid Transporter BGT1 by Tau Tubulin Kinase 2