Why does fever trigger febrile seizures? GABAA receptor gamma2 subunit mutations associated with idiopathic generalized epilepsies have temperature-dependent trafficking deficiencies.

نویسندگان

  • Jing-Qiong Kang
  • Wangzhen Shen
  • Robert L Macdonald
چکیده

With a worldwide incidence as high as 6.7% of children, febrile seizures are one of the most common reasons for seeking pediatric care, but the mechanisms underlying generation of febrile seizures are poorly understood. Febrile seizures have been suspected to have a genetic basis, and recently, mutations in GABAA receptor and sodium channel genes have been identified that are associated with febrile seizures and generalized seizures with febrile seizures plus pedigrees. Pentameric GABAA receptors mediate the majority of fast synaptic inhibition in the brain and are composed of combinations of alpha(1-6), beta(1-3), and gamma(1-3) subunits. In alphabetagamma2 GABAA receptors, the gamma2 subunit is critical for receptor trafficking, clustering, and synaptic maintenance, and mutations in the gamma2 subunit have been monogenically associated with autosomal dominant transmission of febrile seizures. Here, we report that whereas trafficking of wild-type alpha1beta2gamma2 receptors was slightly temperature dependent, trafficking of mutant alpha1beta2gamma2 receptors containing gamma2 subunit mutations [gamma2(R43Q), gamma2(K289M), and gamma2(Q351X)] associated with febrile seizures was highly temperature dependent. In contrast, trafficking of mutant alpha1beta2gamma2 receptors containing an alpha1 subunit mutation [alpha1(A322D)] not associated with febrile seizures was not highly temperature dependent. Brief increases in temperature from 37 to 40 degrees C rapidly (<10 min) impaired trafficking and/or accelerated endocytosis of heterozygous mutant alpha1beta2gamma2 receptors containing gamma2 subunit mutations associated with febrile seizures but not of wild-type alpha1beta2gamma2 receptors or heterozygous mutant alpha1(A322D)beta2gamma2 receptors, suggesting that febrile seizures may be produced by a temperature-induced dynamic reduction of susceptible mutant surface GABAA receptors in response to fever.

برای دانلود رایگان متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

GABRD encoding a protein for extra- or peri-synaptic GABAA receptors is a susceptibility locus for generalized epilepsies.

A major challenge in understanding complex idiopathic generalized epilepsies has been the characterization of their underlying molecular genetic basis. Here, we report that genetic variation within the GABRD gene, which encodes the GABAA receptor delta subunit, affects GABA current amplitude consistent with a model of polygenic susceptibility to epilepsy in humans. We have found a GABRD Glu177A...

متن کامل

A human mutation in Gabrg2 associated with generalized epilepsy alters the membrane dynamics of GABAA receptors.

Neuronal activity modulates the membrane diffusion of postsynaptic γ-aminobutyric acid (GABA)(A) receptors (GABA(A)Rs), thereby regulating the efficacy of GABAergic synapses. The K289M mutation in GABA(A)Rs subunit γ2 has been associated with the generalized epilepsy with febrile seizures plus (GEFS+) syndrome. This mutation accelerates receptor deactivation and therefore reduces inhibitory syn...

متن کامل

GABA(A) receptor epilepsy mutations.

Idiopathic generalized epilepsy (IGE) syndromes are diseases that are characterized by absence, myoclonic, and/or primary generalized tonic-clonic seizures in the absence of structural brain abnormalities. Although it was long hypothesized that IGE had a genetic basis, only recently have causative genes been identified. Here we review mutations in the GABA(A) receptor alpha1, gamma2, and delta ...

متن کامل

Childhood absence epilepsy and febrile seizures: a family with a GABA(A) receptor mutation.

Although several genes for idiopathic epilepsies from families with simple Mendelian inheritance have been found, genes for the common idiopathic generalized epilepsies, where inheritance is complex, presently are elusive. We studied a large family with epilepsy where the two main phenotypes were childhood absence epilepsy (CAE) and febrile seizures (FS), which offered a special opportunity to ...

متن کامل

The GABRG2 mutation, Q351X, associated with generalized epilepsy with febrile seizures plus, has both loss of function and dominant-negative suppression.

The GABA(A) receptor gamma2 subunit mutation, Q351X, associated with generalized epilepsy with febrile seizures plus (GEFS+), created a loss of function with homozygous expression. However, heterozygous gamma2(+/-) gene deletion mice are seizure free, suggesting that the loss of one GABRG2 allele alone in heterozygous patients may not be sufficient to produce epilepsy. Here we show that the mut...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

عنوان ژورنال:
  • The Journal of neuroscience : the official journal of the Society for Neuroscience

دوره 26 9  شماره 

صفحات  -

تاریخ انتشار 2006