Mutations in SLC12A5 in epilepsy of infancy with migrating focal seizures

Stödberg, Tommy; McTague, Amy; Ruiz, Arnaud; Hirata, Hiromi; Zhen, Juan; Long, Philip; Farabella, Irene; Meyer, Esther; Kawahara, Atsuo; Vassallo, Grace; Stivaros, Stavros; Bjursell, Magnus K.; Stranneheim, Henrik; Tigerschiöld, Stephanie; Persson, Bengt; Bangash, I. Hussain; Das, Krishna; Hughes, Deborah; Lesko, Nicole; Lundeberg, Joakim; Scott, Rod C.; Poduri, Annapurna; Scheffer, Ingrid E.; Smith, H. R.; Gissen, Paul; Schorge, Stephanie; Reith, Maarten E. A.; Topf, Maya; Kullmann, Dimitri M.; Harvey, Robert J.; Wedell, Anna; Kurian, Manju A.

doi:10.1038/ncomms9038

Cited by 150 publications

(166 citation statements)

References 37 publications

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“…shows the location in SLC12A5 of the 2 missense mutations in our patient, and the previously reported 6 missense and 2 in-frame deletion mutations in the 5 patients with EIMFS 10,11. The p.Ser399-Leu mutation is found at the intracellular loop between TM6 and TM7, and p.Arg880Leu is located at the C-terminus following TM12 (Figure 3).…”

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confidence: 77%

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A de novo missense mutation in SLC12A5 found in a compound heterozygote patient with epilepsy of infancy with migrating focal seizures

et al. 2017

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Epilepsy of infancy with migrating focal seizures (EIMFS) is an infantile epileptic encephalopathy characterized by refractory seizures, severe psychomotor delay, and multiple moving epileptic discharges. The genetic etiology of EIMFS is relatively homogeneous with the majority of causative mutations found in KCNT1. Currently, gene panel or whole-exome sequencing is used for testing. To verify the pathogenicity of a variant, co-segregation of the variant and the disorder in a pedigree is important; hence, de novo mutations that are judged to be deleterious may be considered pathogenic because the patients are isolated. In contrast, in cases from non-consanguineous families, genes that cause disorders in a recessive manner should remain as potential candidates. Herein, we performed gene panel sequencing of a patient with EIMFS from a non-consanguineous family, and found a compound heterozygous constellation consisting of a maternally inherited p.Ser399Leu and a de novo p.Arg880Leu in SLC12A5, which encodes the neuronal KCC2 cotransporter. These unique mutations show gene variants that act in a recessive manner may be pathogenic for patients from non-consanguineous families.

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confidence: 77%

“…10 Cl− extrusion as well as inhibited dendritic spine formation. However, our finding shows that patients with EIMFS should be screened for SLC12A5 regardless of In regard to the mechanism by which SLC12A5 mutations cause EIMFS, 2 studies arrived at the same conclusion.…”

Section: Mutation Analysismentioning

confidence: 95%

A de novo missense mutation in SLC12A5 found in a compound heterozygote patient with epilepsy of infancy with migrating focal seizures

et al. 2017

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“…SLC12A transporters participate in epithelial ion transport, modulate inhibitory synaptic transmission, and maintain and regulate cell volume (Haas and Forbush 2000; Markadieu and Delpire 2014; Kahle et al 2015). Human mutations in two Na + -independent K + –Cl − cotransporters KCC2 and KCC3 are involved in generalized idiopathic epilepsy (OMIM #616685) (Kahle et al 2014), early infantile epileptic encephalopathy (OMIM #616645) (Stödberg et al 2015), and peripheral nerve degeneration (OMIM #218000) (Hubner et al 2001; Woo et al 2002; Boettger et al 2003; Uyanik et al 2006; Kahle et al 2016), respectively. Mouse models of these disorders recapitulate the main aspects of the phenotypes (Hubner et al 2001; Howard et al 2002; Woo et al 2002; Boettger et al 2003; Kahle et al 2016).…”

Section: Introductionmentioning

confidence: 99%

A patient with multisystem dysfunction carries a truncation mutation in human SLC12A2, the gene encoding the Na-K-2Cl cotransporter, NKCC1

Delpire

Wolfe

Flores

et al. 2016

Cold Spring Harb Mol Case Stud

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This study describes a 13-yr-old girl with orthostatic intolerance, respiratory weakness, multiple endocrine abnormalities, pancreatic insufficiency, and multiorgan failure involving the gut and bladder. Exome sequencing revealed a de novo, loss-of-function allele in SLC12A2, the gene encoding the Na-K-2Cl cotransporter-1. The 11-bp deletion in exon 22 results in frameshift (p.Val1026Phefs*2) and truncation of the carboxy-terminal tail of the cotransporter. Preliminary studies in heterologous expression systems demonstrate that the mutation leads to a nonfunctional transporter, which is expressed and trafficked to the plasma membrane alongside wild-type NKCC1. The truncated protein, visible at higher molecular sizes, indicates either enhanced dimerization or misfolded aggregate. No significant dominant-negative effect was observed. K+ transport experiments performed in fibroblasts from the patient showed reduced total and NKCC1-mediated K+ influx. The absence of a bumetanide effect on K+ influx in patient fibroblasts only under hypertonic conditions suggests a deficit in NKCC1 regulation. We propose that disruption in NKCC1 function might affect sensory afferents and/or smooth muscle cells, as their functions depend on NKCC1 creating a Cl− gradient across the plasma membrane. This Cl− gradient allows the γ-aminobutyric acid (GABA) receptor or other Cl− channels to depolarize the membrane affecting processes such as neurotransmission or cell contraction. Under this hypothesis, disrupted sensory and smooth muscle function in a diverse set of tissues could explain the patient's phenotype.

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“…Moreover, seizure-related disorders in humans have recently been associated with KCC2 mutations (Kahle et al, 2014; Puskarjov et al, 2014; Stödberg et al, 2015). Deficits in KCC2 expression levels and/or activity also occur in animal models of chronic stress (Hewitt et al, 2009; MacKenzie and Maguire, 2015; Tsukahara et al, 2015, 2016), trauma (Jin et al, 2005), ischemia (Jaenisch et al, 2010), schizophrenia (Hyde et al, 2011) and in peritumoral regions in human brain (Pallud et al, 2014; Semaan et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Compromising KCC2 transporter activity enhances the development of continuous seizure activity

et al. 2016

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Impaired neuronal inhibition has long been associated with the increased probability of seizure occurrence and heightened seizure severity. Fast synaptic inhibition in the brain is primarily mediated by the type A γ-aminobutyric acid receptors (GABAARs), ligand-gated ion channels that can mediate Cl− influx resulting in membrane hyperpolarization and the restriction of neuronal firing. In most adult brain neurons, the K+/Cl− co-transporter-2 (KCC2) establishes hyperpolarizing GABAergic inhibition by maintaining low [Cl−]i. In this study, we sought to understand how decreased KCC2 transport function affects seizure event severity. We impaired KCC2 transport in the 0-Mg2+ ACSF and 4-aminopyridine in vitro models of epileptiform activity in acute mouse brain slices. Experiments with the selective KCC2 inhibitor VU0463271 demonstrated that reduced KCC2 transport increased the duration of SLEs, resulting in non-terminating discharges of clonic-like activity. We also investigated slices obtained from the KCC2-Ser940Ala (S940A) point-mutant mouse, which has a mutation at a known functional phosphorylation site causing behavioral and cellular deficits under hyperexcitable conditions. We recorded from the entorhinal cortex of S940A mouse brain slices in both 0-Mg2+ ACSF and 4-aminopyridine, and demonstrated that loss of the S940 residue increased the susceptibility of continuous clonic-like discharges, an in vitro form of status epilepticus. Our experiments revealed KCC2 transport activity is a critical factor in seizure event duration and mechanisms of termination. Our results highlight the need for therapeutic strategies that potentiate KCC2 transport function in order to decrease seizure event severity and prevent the development of status epilepticus.

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Mutations in SLC12A5 in epilepsy of infancy with migrating focal seizures

Cited by 150 publications

References 37 publications

A de novo missense mutation in SLC12A5 found in a compound heterozygote patient with epilepsy of infancy with migrating focal seizures

A de novo missense mutation in SLC12A5 found in a compound heterozygote patient with epilepsy of infancy with migrating focal seizures

A patient with multisystem dysfunction carries a truncation mutation in human SLC12A2, the gene encoding the Na-K-2Cl cotransporter, NKCC1

Compromising KCC2 transporter activity enhances the development of continuous seizure activity

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