Disruption of Sodium Bicarbonate Transporter SLC4A10 in a Patient With Complex Partial Epilepsy and Mental Retardation

Gurnett, Christina A.; Veile, Rosalie; Zempel, J.A.; Blackburn, Lynn; Lovett, Michael; Bowcock, Anne M.

doi:10.1001/archneur.65.4.550

Cited by 64 publications

(59 citation statements)

References 22 publications

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“…In our cohort, patient 4 had deletion of the entire SCN gene cluster and intractable seizures with onset at 11 weeks, while the rest of the patients have deletions that include SLC4A10, but spare SCN1A, and do not have any confirmed seizure activity. Due to deletion of SLC4A10 these patients may still be at risk for later-onset seizures, as previously reported [Gurnett et al, 2008;Krepischi et al, 2010], although the oldest patient remains seizure-free at 11.5 years.…”

Section: Discussionsupporting

confidence: 52%

Investigation of TBR1 Hemizygosity: Four Individuals with 2q24 Microdeletions

et al. 2012

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TBR1 encodes a transcription factor with critical roles in corticogenesis, including cortical neuron migration and axon pathfinding, establishment of regional and laminar identity of cortical neurons, and control of glutamatergic neuronal cell fate. Based upon TBR1’s role in cortical development, we sought to investigate TBR1 hemizygosity in individuals referred for genetic evaluation of intellectual disability and developmental delay. We describe 4 patients with microdeletions identified by molecular cytogenetic techniques, encompassing TBR1 and spanning 2q24.1q31.1, ranging in size from 2.17 to 12.34 Mb. Only the patient with the largest deletion had a possible cortical malformation. Mild ventriculomegaly is the only common brain anomaly, present in all patients; a Chiari I malformation is seen in 2 patients, and mega cisterna magna is seen in a third. Our findings are consistent with Tbr1 mouse models showing that hemizygosity of the gene requires additional genetic factors for the manifestation of severe structural brain malformations. Other syndromic features are present in these patients, including autism spectrum disorders, ocular colobomas, and craniosynostosis, features that are likely affected by the deletion of genes other than TBR1.

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Section: Discussionsupporting

confidence: 52%

Investigation of TBR1 Hemizygosity: Four Individuals with 2q24 Microdeletions

et al. 2012

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“…A significant downregulation of solute carrier family 4 member 10 (SLC4A10) (P=5.00x10 -5 ), which belongs to a small family of sodium-coupled bicarbonate transporters that regulate the intracellular pH of neurons (25), was also observed. In addition to unlimited cell proliferation, cancer is characterized by an altered cellular environment that promotes tumor cell proliferation and metastasis (26).…”

Section: Discussionmentioning

confidence: 99%

“…Calcium channel proteins have been associated with primary tumors of the colon, lung and skin (23). Certain drugs targeting CACNA1C, including magnesium sulfate and nicardipine, have been reported; magnesium sulfate can be used to inhibit the action potential of muscle cells, thereby reducing the frequency and strength of contractions (24); nicardipine is a potent calcium channel inhibitor with important vasodilatory and antihypertensive characteristics that can be used to enhance the efficacy of certain antitumor agents (25).…”

Section: Discussionmentioning

confidence: 99%

Bioinformatics analysis of gene expression alterations conferring drug resistance in tumor samples from melanoma patients with EGFR-activating BRAF mutations

Wang

et al. 2017

Oncol Lett

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Abstract. Melanoma is a highly malignant tumor of the skin melanocytes. Patients with this cancer have a high frequency (~50%) of oncogenic BRAF mutations, particularly BRAF V600E. Treatments for melanoma often target BRAF mutations or involve mitogen-activated protein kinase kinase/extracellular signal-regulated kinase inhibitors. A major challenge in melanoma treatment is resistance to BRAF inhibitor treatment, which may be enhanced by the BRAF mutation itself and/or epidermal growth factor receptor (EGFR) activation, leading to poor prognosis. However, no effective clinical treatment exists for patients with EGFR-activating feedback. The aim of the present study was to analyze gene expression changes in tumors from patients with EGFR-activating BRAF mutations during development of drug resistance. RNA-seq data was downloaded from the Gene Expression Omnibus (GEO) database for pre-and post-treatment tumor samples from three melanoma patients with EGFR-activating BRAF V600E mutations, and from The Cancer Genome Atlas (TCGA) melanoma database for tumor and non-tumor samples from patients with the BRAF V600E mutation and unknown EGFR activation status. Using functional enrichment and KEGG pathway analyses, the present study analyzed differentially expressed genes (DEGs) between pre-vs. post-treatment data from the GEO database and tumor or non-tumor sample data from the TCGA database. The results of the present study indicated that functional and structural changes to the plasma membrane may be associated with drug resistance. The present study identified 9 DEGs that were significantly different between tumor and non-tumor samples and also between prior to and following treatment. Thus, it was confirmed that patients with EGFR-activating BRAF V600E mutations undergo gene expression changes during disease development, and during therapy. These findings may provide potential directions for melanoma-specific therapy.

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“…In the choroid plexus, the slc4a10 gene product is a main basolateral Na ϩ loader and is most likely necessary for secretion of cerebrospinal fluid because disruption of the slc4a10 in mice leads to decreased brain ventricle sizes (4). In humans, a mutation in the SLC4A10 promoter region resulted in severe complex partial epilepsy and mental retardation (5).…”

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confidence: 99%

Na+-dependent HCO3− Import by the slc4a10 Gene Product Involves Cl− Export

Damkier

Aalkjær

Prætorius

2010

Journal of Biological Chemistry

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The slc4a10 gene encodes an electroneutral Na ؉ -dependent HCO 3 ؊ importer for which the precise mode of action remains unsettled. Tight control of intracellular pH (pH i ) 2 is crucial for maintaining a variety of basic cellular functions (1). Regulation of pH i largely depends on acute intracellular buffering and longer term extrusion or import of acid/base equivalents. Integral plasma membrane proteins such as the Na ϩ -dependent HCO 3 Ϫ transporters from the solute carrier gene family 4 (slc4a) mediate these functions. The slc4a10-gene product is primarily expressed in the central nervous system and is important for normal brain function (2-4). In the choroid plexus, the slc4a10 gene product is a main basolateral Na ϩ loader and is most likely necessary for secretion of cerebrospinal fluid because disruption of the slc4a10 in mice leads to decreased brain ventricle sizes (4). In humans, a mutation in the SLC4A10 promoter region resulted in severe complex partial epilepsy and mental retardation (5).Within the gene family, slc4a10 shares the highest amino acid homology with the electroneutral Na ϩ :HCO 3 Ϫ cotransporter Nbcn1 (slc4a7) and the Na ϩ -dependent Cl Ϫ /HCO 3 Ϫ exchanger, Ndcbe (slc4a8). The transport mode of the slc4a10 gene product has been investigated by more research groups defining the protein as an electroneutral Na ϩ and HCO 3 Ϫ -dependent transporter which is inhibited by 4,4Ј-diisothiocyanatostilbene-2,2Ј-disulfonate (DIDS) (2, 6, 7). The studies, however, differ in opinion regarding the involvement of Cl Ϫ in the transport process. Thus, the human SLC4A10 gene product, first designated with the abbreviation Ncbe for Na ϩ -dependent Cl Ϫ /HCO 3 Ϫ exchanger (2), was recently suggested renamed as Nbcn2 for electroneutral Na ϩ :HCO 3 Ϫ cotransporter 2, displaying Cl Ϫ /Cl Ϫ self-exchange instead of Cl Ϫ /HCO 3 Ϫ exchange activity (7). The knowledge on the primary structure of the slc4a10-derived protein is not sufficient to suggest which parts of the transmembrane region are involved in ion translocation and can, thus, not help predict the mode of action for this Na ϩ -dependent HCO 3 Ϫ transporter. More structure-function data are available on the anion exchanger Ae1 (slc4a1), which seems to present two hinge-like loops within the transmembrane region with access to both the extra-and intracellular environment (8). These loops were proposed to be involved in attraction and perhaps even translocation of ions by Ae1.In this investigation, we aimed to define the transport mode of the slc4a10 gene product by analyzing the targeted ionic and structural requirements for transport by the protein. The study was conducted on mammalian NIH-3T3 fibroblasts devoid of endogenous Na ϩ -dependent HCO 3 Ϫ transport stably transfected with single copies of the coding region of rodent slc4a10. We found three lines of evidence for the functional involvement of Cl Ϫ in transport by the slc4a10-derived protein: (i) the Na ϩ :HCO 3 Ϫ stoichiometry was estimated to 1:2; (ii) Na ϩ -dependent pH i regulation was de...

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Disruption of Sodium Bicarbonate Transporter SLC4A10 in a Patient With Complex Partial Epilepsy and Mental Retardation

Cited by 64 publications

References 22 publications

Investigation of TBR1 Hemizygosity: Four Individuals with 2q24 Microdeletions

Investigation of TBR1 Hemizygosity: Four Individuals with 2q24 Microdeletions

Bioinformatics analysis of gene expression alterations conferring drug resistance in tumor samples from melanoma patients with EGFR-activating BRAF mutations

Na+-dependent HCO3− Import by the slc4a10 Gene Product Involves Cl− Export

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