Neonatal developmental and epileptic encephalopathy due to autosomal recessive variants in <i>SLC13A5</i> gene

Matricardi, Sara; Liso, Paola De; Freri, Elena; Costa, Paola; Castellotti, Barbara; Magri, Stefania; Gellera, Cinzia; Granata, Tiziana; Musante, Luciana; Lesca, Gaëtan; Oertel, Julie; Craiu, Dana; Hammer, Trine Bjørg; Møller, Rikke S.; Barišić, Nina; Jamra, Rami Abou; Polster, Tilman; Vigevano, Federico; Marini, Carla

doi:10.1111/epi.16699

Cited by 36 publications

(56 citation statements)

References 23 publications

(159 reference statements)

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“…Functional impacts of NaCT inhibition or knockdown have been proposed in cells, though findings are not necessarily dependent on the presence of extracellular citrate (Li et al, 2017;Phokrai et al, 2018;Poolsri et al, 2018). Citrate transport may also influence AcCoA metabolism and ionic homeostasis in the nervous system, as loss-of-function mutations in SLC13A5 have been linked to pediatric epilepsy, Kohlschütter-Tönz syndrome, and other brain disorders (Hardies et al, 2015;Klotz et al, 2016;Matricardi et al, 2020;Schossig et al, 2017;Thevenon et al, 2014). Notably, citrate levels were significantly increased in plasma and cerebrospinal fluid (CSF) in such epilepsy patients (Bainbridge et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

NaCT (SLC13A5) facilitates citrate import and metabolism under nutrient-limited conditions

Kumar

Cordes

Thalacker‐Mercer

et al. 2021

Preprint

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Citrate lies at a critical node of metabolism linking tricarboxylic acid metabolism and fatty acid synthesis via acetyl-coenzyme A. Recent studies have linked the sodium citrate transporter (NaCT), encoded by SLC13A5, to dysregulated hepatic metabolism and pediatric epilepsy. To examine how NaCT-mediated citrate metabolism contributes to the pathophysiology of these diseases we applied 13C isotope tracing to SLC13A5-deficient hepatocellular carcinoma (HCC) cell lines and primary rat cortical neurons. Exogenous citrate contributed to intermediary metabolism at appreciable levels only under hypoxic conditions. In the absence of glutamine, citrate supplementation increased de novo lipogenesis and growth of HCC cells. Knockout of SLC13A5 in Huh7 cells compromised citrate uptake and catabolism. Citrate supplementation rescued Huh7 cell viability in response to glutamine deprivation and Zn2+ treatment, and these effects were mitigated by NaCT deficiency. Collectively, these findings demonstrate that NaCT-mediated citrate uptake is metabolically important under nutrient limited conditions and may facilitate resistance to metal toxicity.

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Section: Introductionmentioning

confidence: 99%

NaCT (SLC13A5) facilitates citrate import and metabolism under nutrient-limited conditions

Kumar

Cordes

Thalacker‐Mercer

et al. 2021

Preprint

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“…Biallelic LoF variants in SLC13A5 cause DEE25 characterized by neonatal‐onset epilepsy with fever‐sensitivity, recurrent status epilepticus, global developmental delay/intellectual disability in addition to variable neurological features including ataxia, microcephaly, choreoathetosis and spasticity (Hardies et al, 2015; Klotz et al, 2016; Kopel et al, 2017; Matricardi et al, 2020; Schossig et al, 2017; Thevenon et al, 2014). The three affected siblings have the aforementioned features with profound GDD/ID although only one affected child, the eldest (BAB12492), had microcephaly (defined as OFC < −2 SD ) while the other two had borderline microcephaly (−1.65 SD and z = −1.95 SD ) thus fitting into the spectrum of SLC13A5 ‐related disorders.…”

Section: Discussionmentioning

confidence: 99%

A novel homozygous SLC13A5 whole‐gene deletion generated by Alu/Alu‐mediated rearrangement in an Iraqi family with epileptic encephalopathy

Duan

Saadi

Grochowski

et al. 2021

American J of Med Genetics Pt A

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Biallelic loss‐of‐function (LoF) of SLC13A5 (solute carrier family 13, member 5) induced deficiency in sodium/citrate transporter (NaCT) causes autosomal recessive developmental epileptic encephalopathy 25 with hypoplastic amelogenesis imperfecta (DEE25; MIM #615905). Many pathogenic SLC13A5 single nucleotide variants (SNVs) and small indels have been described; however, no cases with copy number variants (CNVs) have been sufficiently investigated. We describe a consanguineous Iraqi family harboring an 88.5 kb homozygous deletion including SLC13A5 in Chr17p13.1. The three affected male siblings exhibit neonatal‐onset epilepsy with fever‐sensitivity, recurrent status epilepticus, global developmental delay/intellectual disability (GDD/ID), and other variable neurological findings as shared phenotypical features of DEE25. Two of the three affected subjects exhibit hypoplastic amelogenesis imperfecta (AI), while the proband shows no evidence of dental abnormalities or AI at 2 years of age with apparently unaffected primary dentition. Characterization of the genomic architecture at this locus revealed evidence for genomic instability generated by an Alu/Alu‐mediated rearrangement; confirmed by break‐point junction Sanger sequencing. This multiplex family from a distinct population elucidates the phenotypic consequence of complete LoF of SLC13A5 and illustrates the importance of read‐depth‐based CNV detection in comprehensive exome sequencing analysis to solve cases that otherwise remain molecularly unsolved.

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“…Yamamoto et al [2017], Wang et al [2017], Stringer et al [2020] and Brenner et al [2019 demonstrated that that the expression of SPP1, C5AR1, CACNA1H and CACNA1A are associated with the prognosis of amyotrophic lateral sclerosis, but these genes might be associated with advancement of dementia. TGFBR1 [Zheng et al 2021], SCN4A [Bergareche et al 2015], KCNT1 [McTague et al 2018], SLC13A5 [Matricardi et al 2020] and CACNA1B [Gorman et al 2019] were reported to be associated with progression of epilepsy, but these genes might be involved in dementia.…”

Section: Discussionmentioning

confidence: 99%

Identification of Key Pathways and Genes in Dementia via Integrated Bioinformatics Analysis

Vastrad¹,

Vastrad²

2021

Preprint

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To provide a better understanding of dementia at the molecular level, this study aimed to identify the genes and key pathways associated with dementia by using integrated bioinformatics analysis. Based on the expression profiling by high throughput sequencing dataset GSE153960 derived from the Gene Expression Omnibus (GEO), the differentially expressed genes (DEGs) between patients with dementia and healthy controls were identified. With DEGs, we performed a series of functional enrichment analyses. Then, a protein protein interaction (PPI) network, modules, miRNA hub gene regulatory network and TF hub gene regulatory network was constructed, analyzed and visualized, with which the hub genes miRNAs and TFs nodes were screened out. Finally, validation of hub genes was performed by using receiver operating characteristic curve (ROC) analysis and RT PCR. A total of 948 DEGs were screened out, among which 475 genes were up regulated; while 473 were down regulated. Functional enrichment analyses indicated that DEGs were mainly involved in defense response, ion transport, neutrophil degranulation and neuronal system. The hub genes (CDK1, TOP2A, MAD2L1, RSL24D1, CDKN1A, NOTCH3, MYB, PWP2, WNT7B and HSPA12B) were identified from PPI network, modules, miRNA hub gene regulatory network and TF hub gene regulatory network. We identified a series of key genes along with the pathways that were most closely related with dementia initiation and progression. Our results provide a more detailed molecular mechanism for the advancement of dementia, shedding light on the potential biomarkers and therapeutic targets.

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Neonatal developmental and epileptic encephalopathy due to autosomal recessive variants in SLC13A5 gene

Cited by 36 publications

References 23 publications

NaCT (SLC13A5) facilitates citrate import and metabolism under nutrient-limited conditions

NaCT (SLC13A5) facilitates citrate import and metabolism under nutrient-limited conditions

A novel homozygous SLC13A5 whole‐gene deletion generated by Alu/Alu‐mediated rearrangement in an Iraqi family with epileptic encephalopathy

Identification of Key Pathways and Genes in Dementia via Integrated Bioinformatics Analysis

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