Skip to main content
Log in

Rare SLC1A1 variants in hot water epilepsy

  • Original Investigation
  • Published:
Human Genetics Aims and scope Submit manuscript

Abstract

Hot water epilepsy is sensory epilepsy, wherein seizures are triggered by an unusual stimulus: contact with hot water. Although genetic factors contribute to the etiology of hot water epilepsy, molecular underpinnings of the disorder remain largely unknown. We aimed to identify the molecular genetic basis of the disorder by studying families with two or more of their members affected with hot water epilepsy. Using a combination of genome-wide linkage mapping and whole exome sequencing, a missense variant was identified in SLC1A1 in a three-generation family. Further, we examined SLC1A1in probands of 98 apparently unrelated HWE families with positive histories of seizures provoked by contact with hot water. In doing so, we found three rare variants, p.Asp174Asn, p.Val251Ile and p.Ile304Met in the gene. SLC1A1 is a neuronal glutamate transporter which limits excitotoxicity and its loss-of-function leads to age-dependent neurodegeneration. We examined functional attributes of the variants in cultured mammalian cells. All three non-synonymous variants affected glutamate uptake, exhibited altered glutamate kinetics and anion conductance properties of SLC1A1. These observations provide insights into the molecular basis of hot water epilepsy and show the role of SLC1A1 variants in this intriguing neurobehavioral disorder.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR (2010) A method and server for predicting damaging missense mutations. Nat Methods 7:248–249

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Allen IM (1945) Observations on cases of reflex epilepsy. NZ Med J 44:135–142

    Google Scholar 

  • Aoyama K, Suh SW, Hamby AM, Liu J, Chan WY, Chen Y, Swanson RA (2006) Neuronal glutathione deficiency and age-dependent neurodegeneration in the EAAC1 deficient mouse. Nat Neurosci 9:119–126

    Article  CAS  PubMed  Google Scholar 

  • Arriza JL, Fairman WA, Wadiche JI, Murdoch GH, Kavanaugh MP, Amara SG (1994) Functional comparisons of three glutamate transporter subtypes cloned from human motor cortex. J Neurosci 14:5559–5569

    CAS  PubMed  Google Scholar 

  • Bailey CG, Ryan RM, Thoeng AD, Ng C, King K, Vanslambrouck JM, Auray-Blais C, Vandenberg RJ, Bröer S, Rasko JE (2011) Loss-of-function mutations in the glutamate transporter SLC1A1 cause human dicarboxylic aminoaciduria. J Clin Investig 121:446–453

    Article  CAS  PubMed  Google Scholar 

  • Bebek N, Gürses C, Gokyigit A, Baykan B, Ozkara C, Dervent A (2001) Hot water epilepsy: clinical and electrophysiologic findings based on 21 cases. Epilepsia 42:1180–1184

    Article  CAS  PubMed  Google Scholar 

  • Billups B, Rossi D, Attwell D (1996) Anion conductance behavior of the glutamate uptake carrier in salamander retinal glial cells. J Neurosci 16:6722–6731

    CAS  PubMed  Google Scholar 

  • Burg MG, Wu CF (2012) Mechanical and temperature stressors-induced seizure-and-paralysis behaviors in Drosophila bang-sensitive mutants. J Neurogenet 26:189–197

    Article  PubMed  PubMed Central  Google Scholar 

  • Chen Y, Swanson RA (2003) The glutamate transporters EAAT2 and EAAT3 mediate cysteine uptake in cortical neuron cultures. J Neurochem 84:1332–1339

    Article  CAS  PubMed  Google Scholar 

  • Choi DW (1992) Excitotoxic cell death. J Neurobiol 23:1261–1276

    Article  CAS  PubMed  Google Scholar 

  • Clements JD (1996) Transmitter time course in the synaptic cleft: its role in central synaptic function. Trends Neurosci 19:163–171

    Article  CAS  PubMed  Google Scholar 

  • Clements JD, Lester RA, Tong G, Jahr CE, Westbrook GL (1992) The time course of glutamate in the synaptic cleft. Science 258:1498–1501

    Article  CAS  PubMed  Google Scholar 

  • Danbolt NC (2001) Glutamate uptake. Prog Neurobiol 65:1–105

    Article  CAS  PubMed  Google Scholar 

  • Ferlazzo E, Zifkin BG, Andermann E, Andermann F (2005) Cortical triggers in generalized reflex seizures and epilepsies. Brain 128:700–710

    Article  PubMed  Google Scholar 

  • Grewer C, Balani P, Weidenfeller C, Bartusel T, Tao Z, Rauen T (2005) Individual subunits of the glutamate transporter EAAC1 homotrimer function independently of each other. Biochemistry 44:11913–11923

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grewer C, Gameiro A, Rauen T (2014) SLC1 glutamate transporters. Pflug Arch 466:3–24

    Article  CAS  Google Scholar 

  • Hamberger A et al (1983) Extracellular GABA, glutamate and glutamine in vivo -perfusion-dialysis of the rabbit hippocampus. Neurol Neurobiol 7:473–492

    CAS  Google Scholar 

  • Holmseth S, Dehnes Y, Huang YH, Follin-Arbelet VV, Grutle NJ, Mylonakou MN, Plachez C, Zhou Y, Furness DN, Bergles DE, Lehre KP, Danbolt NC (2012) The density of EAAC1 (EAAT3) glutamate transporters expressed by neurons in the mammalian CNS. J Neurosci 32:6000–6013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Humphray SJ, Oliver K, Hunt AR, Plumb RW, Loveland JE, Howe KL, Andrews TD, Searle S, Hunt SE, Scott CE et al (2004) DNA sequence and analysis of human chromosome 9. Nature 429:369–374

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Keipert JA (1969) Epilepsy precipitated by bathing: water-immersion epilepsy. Aust Paediatr J 5:244–247

    Google Scholar 

  • Kruglyak L, Daly MJ, Reeve-Daly MP, Lander ES (1996) Parametric and nonparametric linkage analysis: a unified multipoint approach. Am J Hum Genet 58:1347–1363

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kurata S (1979) Epilepsy precipitated by bathing-A follow-up study. Brain Dev (Domestic ed) 11:400–405

    Google Scholar 

  • Lenoir P, Ramet J, Meirleir DL, D’Allest AM, Desprechins B, Loeb H (1989) Bathing-induced seizures. Pediatr Neurol 5:124–125

    Article  CAS  PubMed  Google Scholar 

  • Li H, Durbin R (2009) Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25:1754–1760

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, Marth G, Abecasis G, Durbin R, 1000 Genome Project Data Processing Subgroup (2009) The sequence alignment/map format and SAM tools. Bioinformatics 25:2077–2078

    CAS  Google Scholar 

  • Lin CL, Orlov I, Ruggiero AM, Dykes-Hoberg M, Lee A, Jackson M, Rothstein JD (2001) Modulation of the neuronal glutamate transporter EAAC1 by the interacting protein GTRAP3-18. Nature 410:84–88

    Article  CAS  PubMed  Google Scholar 

  • Machtens JP, Kortzak D, Lansche C, Leinenweber A, Kilian P, Begemann B, Zachariae U, Ewers D, de Groot BL, Briones R, Fahlke C (2015) Mechanisms of anion conduction by coupled glutamate transporters. Cell 160:542–553

    Article  CAS  PubMed  Google Scholar 

  • Mani KS, Mani AJ, Ramesh CK (1974) Hot-water epilepsy–a peculiar type of reflex epilepsy: clinical and EEG features in 108 cases. Trans Am Neurol Assoc 99:224–226

    CAS  PubMed  Google Scholar 

  • Mofenson HC, Weymuller CA, Greensher J (1965) Epilepsy due to water immersion: an unusual case of reflex sensory epilepsy. JAMA 191:600–601

    Article  CAS  PubMed  Google Scholar 

  • Moran J (1976) So-called water immersion epilepsy. Ir J Med Sci 145:140

    Google Scholar 

  • Morimoto T, Hayakawa T, Sugie H, Awaya Y, Fukuyama Y (1985) Epileptic seizures precipitated by constant light, movement in daily life, and hot water immersion. Epilepsia 26:237–242

    Article  CAS  PubMed  Google Scholar 

  • Myles-Worsley M, Tiobech J, Browning SR, Korn J, Goodman S, Gentile K, Melhem N, Byerley W, Faraone SV, Middleton FA (2013) Deletion at the SLC1A1 glutamate transporter gene co-segregates with schizophrenia and bipolar schizoaffective disorder in a 5-generation family. Am J Med Genet B Neuropsychiatr Genet 162B:87–95

    Article  PubMed  Google Scholar 

  • Ng PC, Henikoff S (2003) SIFT: predicting amino acid changes that affect protein function. Nucleic Acids Res 31:3812–3814

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nguyen DK, Rouleau I, Sénéchal G, Ansaldo AI, Gravel M, Benfenati F, Cossette P (2015) X-linked focal epilepsy with reflex bathing seizures: characterization of a distinct epileptic syndrome. Epilepsia 56:1098–1108

    Article  CAS  PubMed  Google Scholar 

  • Plouin P, Vigevano F (2004) Reflex seizures in infancy. In: Wolf P, Inoue Y, Zifkin B (eds) Reflex epilepsies: progress in understanding. J Libbey Eurotext, Montrouge, pp 115–122

    Google Scholar 

  • Ratnapriya R, Satishchandra P, Kumar SD, Gadre G, Reddy R, Anand A (2009a) A locus for autosomal dominant reflex epilepsy precipitated by hot water maps at chromosome 10q21.3-q22.3. Hum Genet 125:541–549

    Article  PubMed  Google Scholar 

  • Ratnapriya R, Satishchandra P, Dilip S, Gadre G, Anand A (2009b) Familial autosomal dominant reflex epilepsy triggered by hot water maps to 4q24-q28. Hum Genet 126:677–683

    Article  CAS  PubMed  Google Scholar 

  • Sala G, Beretta S, Ceresa C, Mattavelli L, Zoia C, Tremolizzo L, Ferri A, Carrì MT, Ferrarese C (2005) Impairment of glutamate transport and increased vulnerability to oxidative stress in neuroblastoma SH-SY5Y cells expressing a Cu, Zn superoxide dismutase typical of familial amyotrophic lateral sclerosis. Neurochem Int 46:227–234

    Article  CAS  PubMed  Google Scholar 

  • Samuels J, Wang Y, Riddle MA, Greenberg BD, Fyer AJ, McCracken JT, Rauch SL, Murphy DL, Grados MA, Knowles JA et al (2011) Comprehensive family-based association study of the glutamate transporter gene SLC1A1 in obsessive-compulsive disorder. Am J Med Genet 4:472–477

    Article  Google Scholar 

  • Santos-Silva R, Passas A, Rocha C, Figueiredo R, Mendes-Ribeiro J, Fernandes S, Biskup S, Leão M (2015) Bilateral frontoparietal polymicrogyria: a novel GPR56 mutation and an unusual phenotype. Neuropediatrics 46:134–138

    Article  CAS  PubMed  Google Scholar 

  • Satishchandra P (2003) Hot-water epilepsy. Epilepsia 44(Suppl. 1):29–32

    Article  PubMed  Google Scholar 

  • Satishchandra P, Shivaramakrishna A, Kaliaperumal VG, Schoenberg BS (1988) Hot water epilepsy: a variant of reflex epilepsy in Southern India. Epilepsia 29:52–56

    Article  CAS  PubMed  Google Scholar 

  • Satishchandra P, Dilipkumar S, Subbakrishna DK, Sinha S (2014) Intermittent clobazam prophylaxis in hot water epilepsy is safe and effective: a prospective study. Epilepsy Res 108:1238–1242

    Article  CAS  PubMed  Google Scholar 

  • Schwarz JM, Cooper DN, Schuelke M, Seelow D (2014) MutationTaster2: mutation prediction for the deep-sequencing age. Nat Methods 11:361–362

    Article  CAS  PubMed  Google Scholar 

  • Sepkuty JP, Cohen AS, Eccles C, Rafiq A, Behar K, Ganel R, Coulter DA, Rothstein JD (2002) A neuronal glutamate transporter contributes to neurotransmitter GABA synthesis and epilepsy. J Neurosci 22:6372–6379

    CAS  PubMed  PubMed Central  Google Scholar 

  • Shaw NJ, Livingston JH, Minns RA, Clarke M (1988) Epilepsy precipitated by bathing. Dev Med Child Neurol 30:108–111

    Article  CAS  PubMed  Google Scholar 

  • Stensman K, Ursing B (1971) Epilepsy precipitated by hot water immersion. Neurology 21:559–562

    Article  CAS  PubMed  Google Scholar 

  • Szymonowicz W, Meloff KL (1978) Hot-water epilepsy. Can J Neurol Sci 5:247–251

    Article  CAS  PubMed  Google Scholar 

  • Tao Z, Zhang Z, Grewer C (2006) Neutralization of the aspartic acid residue Asp-367, but not Asp-454, inhibits binding of Na+ to the glutamate-free form and cycling of the glutamate transporter EAAC1. J Biol Chem 281:10263–10272

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Watzke N, Grewer C (2001) The anion conductance of the glutamate transporter EAAC1 depends on the direction of glutamate transport. FEBS Lett 503:121–125

    Article  CAS  PubMed  Google Scholar 

  • Wolf P, Koepp M (2012) Reflex epilepsies. In: Stefan H, Theodore WH (eds) Handbook of Clinical Neurology, Part I, vol 107., Epilepsy Elsevier, Edinburgh, pp 257–276

    Google Scholar 

  • Won SJ, Yoo BH, Brennan AM, Shin BS, Kauppinen TM, Berman AE, Swanson RA, Suh SW (2010) EAAC1 gene deletion alters zinc homeostasis and exacerbates neuronal injury after transient cerebral ischemia. J Neurosci 30:15409–15418

    Article  CAS  PubMed  Google Scholar 

  • Zoia C, Cogliati T, Tagliabue E, Cavaletti G, Sala G, Galimberti G, Rivolta I, Rossi V, Frattola L, Ferrarese C (2004) Glutamate transporters in platelets: eAAT1 decrease in aging and in Alzheimer’s disease. Neurobiol Aging 25:149–157

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We are grateful to individuals with hot water epilepsy and their families for their participation in the study. We thank Hemalatha Balaram, James Chelliah and Sharat Chandra for inputs and comments on the manuscript. We acknowledge suggestions by Hemalatha Balaram on the glutamate uptake kinetics experiments and Rahul Ghugari for help with gene sequencing among control individuals. This work is supported by funding from ICMR, New Delhi and JNCASR, Bangalore. KRK acknowledges receipt of a research fellowship from UGC-CSIR, New Delhi.

Author contribution

PS and AA conceived the study. KRK, PS and AA participated in the study design. PS and SS recruited hot water epilepsy families. KRK performed experiments. KRK and AA analyzed and interpreted the data. KRK and AA drafted the manuscript. KRK, PS, SS and AA edited the manuscript. PS and SS had full access to the data in the study and take responsibility of the data accuracy and analysis. All the authors have approved the final manuscript

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Anuranjan Anand.

Ethics declarations

Conflict of interest

All authors report no financial interests or potential conflicts of interests.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 382 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Karan, K.R., Satishchandra, P., Sinha, S. et al. Rare SLC1A1 variants in hot water epilepsy. Hum Genet 136, 693–703 (2017). https://doi.org/10.1007/s00439-017-1778-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00439-017-1778-7

Keywords

Navigation