Rare SLC1A1 variants in hot water epilepsy.
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.
Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR), Bangalore, 560 064, India.
Kalpita Rashimi
KR
Karan
Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, 560 029, India.
P
P
Satishchandra
Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, 560 029, India.
Sanjib
S
Sinha
Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR), Bangalore, 560 064, India. anand@jncasr.ac.in.
Anuranjan
A
Anand
D000595:Amino Acid Sequence; D000818:Animals; D004827:Epilepsy / Q000209:etiology / Q000235:genetics*; D050580:Excitatory Amino Acid Transporter 3 / Q000737:chemistry / Q000235:genetics*; D059472:Exome; D005260:Female; D008040:Genetic Linkage; D006358:Hot Temperature; D006801:Humans; D008297:Male; D018408:Patch-Clamp Techniques; D010375:Pedigree; D017386:Sequence Homology, Amino Acid; D014867:Water
D050580:Excitatory Amino Acid Transporter 3; C493400:SLC1A1 protein, human; D014867:Water