Estimated carrier frequency of creatine transporter deficiency in females in the general population using functional characterization of novel missense variants in the SLC6A8 gene

Desroches, Caro Lyne; Patel, Jaina; Wang, Peixiang; Minassian, Berge A.; Salomons, Gajja S.; Marshall, Christian R.; Mercimek-Mahmutoglu, Saadet

doi:10.1016/j.gene.2015.04.011

Cited by 29 publications

(18 citation statements)

References 26 publications

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“…The most common cause of Cr deficiency is due the loss of the SLC6A8 gene (Cr transporter; CrT) . The exact incidence of CrT deficiency (CTD) has been difficult to ascertain due to limitations of public databases, but the limited number of studies have suggested that CTD accounts for 0.2 to 5.4% of males with intellectual disability . Unlike defects in Cr synthesis, CTD cannot be treated with oral Cr supplementation or Cr synthesis precursors .…”

Section: Introductionmentioning

confidence: 99%

“…3,4 The exact incidence of CrT deficiency (CTD) has been difficult to ascertain due to limitations of public databases, but the limited number of studies have suggested that CTD accounts for 0.2 to 5.4% of males with intellectual disability. [5][6][7][8][9] Unlike defects in Cr synthesis, CTD cannot be treated with oral Cr supplementation 10 or Cr synthesis precursors. [11][12][13] The inability to restore Cr in CTD makes the development of molecules that could deliver Cr past the blood-brain barrier 14 or Cr mimetics 15 valuable as possible treatment strategies.…”

Section: Introductionmentioning

confidence: 99%

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Deletion of the creatine transporter gene in neonatal, but not adult, mice leads to cognitive deficits

Udobi

Delcimmuto

Kokenge

et al. 2019

J of Inher Metab Disea

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Creatine (Cr) is a guanidino compound that provides readily available phosphate pools for the regeneration of spent adenosine triphosphate (ATP). The lack of brain Cr causes moderate to severe intellectual disability, language impairment, and epilepsy. The most prevalent cause of Cr deficiency are mutations in the X‐linked SLC6A8 (Creatine transporter; CrT) gene, known as CrT deficiency (CTD). One of the most critical areas that need to be addressed is whether Cr is necessary for brain development. To address this concern, the Slc6a8 gene was knocked out in either neonatal (postnatal day (P)5) or adult (P60) mice using a tamoxifen‐inducible Cre recombinase driven by the human ubiquitin C (UBC) promoter. Mice were tested in the Morris water maze, novel, object recognition, and conditioned fear 60 days after Slc6a8 deletion. In addition, overnight locomotor activity was analyzed. Mice that had the gene deleted on P5 showed deficits in the Morris water maze and novel object recognition, while there were no deficits in P60 knockout mice. Interestingly, the P5 knockout mice showed hyperactivity during the dark phase; however, when examining control mice, the effect was due to the administration of tamoxifen from P5 to 10. Taken together, the results of this study show that Cr is necessary during periods of brain development involved in spatial and object learning. This study also highlights the continued importance of using proper control groups for behavioral testing.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Deletion of the creatine transporter gene in neonatal, but not adult, mice leads to cognitive deficits

Udobi

Delcimmuto

Kokenge

et al. 2019

J of Inher Metab Disea

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“…The prevalence in family cases is 5.4% [ 5 , 13 , 21 ]. The estimated carrier frequency of CRTR-D is 0.024% in females in the general population [ 22 ]. A total of 142 SLC6A8 variants have been reported in 667 individuals (according to the LOVD SLC6A8 database), which mainly in Western populations.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2018

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BackgroundX-linked creatine transporter deficiency (OMIM#300036,CRTR-D) is characterized by cerebral creatine deficiency, intellectual disabilities, severe speech impairment, seizures and behavioral problems. Mutations in the creatine transporter gene SLC6A8, a member of the solute-carrier family 6 mapped to Xq28, have been reported to cause the creatine transporter deficiency.Case presentationThe proband presented at 5 yrs. 1 month of age with delays in intellectual and development, seizures and behavioral problems. A novel missense mutation, c.1181C > A (p.Thr394Lys), in the SLC6A8 gene (NM_005629.3) was detected via targeted exome sequencing, and then validated by Sanger sequencing. Multiple in silico variant effect analysis methods, including SIFT, PolyPhen2, PROVEAN, and Mutation Taster predicted that this variant was likely damaging or diseasing-causing. This hemizygous variation was also identified in the affected brother with the same clinical condition and inherited from the heterozygous carrier mother. The diagnosis was suggested by increased urinary creatine/creatinine (Cr:Crn) ratio and markedly reduced creatine content peak by brain proton magnetic resonance spectroscopy (MRS). The proband’s mother became pregnant with a 3rd sibling, in whom the Sanger sequencing result of c.1181C > A was negative.ConclusionThe novel mutation c.1181C > A in the SLC6A8 gene reported in a Chinese family has expanded the mutation spectrum of CRTR-D. The combination of powerful new technologies such as targeted exome sequencing with thorough systematic clinical evaluation of patients will improve the diagnostic yield, and assist in genetic counselling and prenatal diagnosis for suspected genetic disorders.Electronic supplementary materialThe online version of this article (10.1186/s12881-018-0707-5) contains supplementary material, which is available to authorized users.

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“…Truncations due to premature stop codons were ignored, as were mutations, which resulted in a disrupted binding site for substrate and co-substrate ions. The pertinent references are for the norepinephrine transport (NET/SLC6A2 [ 17 ], for the creatine transporter-1 (CT1/SLC6A8 [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 ]), for the glycine transporter-2 (GlyT2/SLC6A5 [ 29 , 30 ]), for the dopamine transporter (DAT/SLC6A3 [ 31 , 32 , 33 ]) and for the GABA-transporter-1 (GAT1 [ 34 ]).…”

Section: Figurementioning

confidence: 99%

Relax, Cool Down and Scaffold: How to Restore Surface Expression of Folding-Deficient Mutant GPCRs and SLC6 Transporters

Asjad

Nasrollahi-Shirazi

Sučić

et al. 2017

IJMS

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Many diseases arise from mutations, which impair protein folding. The study of folding-deficient variants of G protein-coupled receptors and solute carrier 6 (SLC6) transporters has shed light on the folding trajectory, how it is monitored and how misfolding can be remedied. Reducing the temperature lowers the energy barrier between folding intermediates and thereby eliminates stalling along the folding trajectory. For obvious reasons, cooling down is not a therapeutic option. One approach to rescue misfolded variants is to use membrane-permeable orthosteric ligands. Antagonists of GPCRs are—in many instances—effective pharmacochaperones: they restore cell surface expression provided that they enter cells and bind to folding intermediates. Pharmacochaperoning of SLC6 transporters is less readily achieved because the ionic conditions in the endoplasmic reticulum (ER) are not conducive to binding of typical inhibitors. The second approach is to target the heat-shock protein (HSP) relay, which monitors the folding trajectory on the cytosolic side. Importantly, orthosteric ligands and HSP-inhibitors are not mutually exclusive. In fact, pharmacochaperones and HSP-inhibitors can act in an additive or synergistic manner. This was exemplified by rescuing disease-causing, folding-deficient variants of the human dopamine transporters with the HSP70 inhibitor pifithrin-μ and the pharmacochaperone noribogaine in Drosophila melanogaster.

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Estimated carrier frequency of creatine transporter deficiency in females in the general population using functional characterization of novel missense variants in the SLC6A8 gene

Cited by 29 publications

References 26 publications

Deletion of the creatine transporter gene in neonatal, but not adult, mice leads to cognitive deficits

Deletion of the creatine transporter gene in neonatal, but not adult, mice leads to cognitive deficits

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

Relax, Cool Down and Scaffold: How to Restore Surface Expression of Folding-Deficient Mutant GPCRs and SLC6 Transporters

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