Background: Transporters, ion pumps, and ion channels are membrane proteins that regulate selective permeability and maintain ionic gradients across cell membranes. Mutations in CACNA1A encoding a neuronal calcium cha...Background: Transporters, ion pumps, and ion channels are membrane proteins that regulate selective permeability and maintain ionic gradients across cell membranes. Mutations in CACNA1A encoding a neuronal calcium channel and ATP1A2 encoding an ion pump cause episodic ataxia, hemiplegic migraine, and seizures. Mutant gene products of both CACNA1A and ATP1A2 may affect neurotransmission of glutamate, the most abundant excitatory amino acid neurotransmitter. Methods: We examined our patient population with episodic ataxia and hemiplegic migraine but with no mutation in either CACNA1A or ATP1A2. We looked for mutations in SLC1A3, which encodes the glutamate transporter excitatory amino acid transporter (EAAT) 1 that is important in removing glutamate from the synaptic cleft. Results: A patient with episodic ataxia, seizures, migraine, and alternating hemiplegia has a heterozygous mutation in SLC1A3 that is not present in his asymptomatic parents and controls. Expression studies of the mutant EAAT1 showed decreased expression of the protein with a markedly reduced capacity for glutamate uptake. When coexpressed, the mutant EAAT1 decreased the activity of wild-type EAAT1 but not of two other transporters EAAT2 or EAAT3, suggesting that mutant EAAT1 specifically multimerizes with wild-type EAAT1 to exert its dominant negative effect. Conclusion: Our data show that a heterozygous mutation in EAAT1 can lead to decreased glutamate uptake, which can contribute to neuronal hyperexcitability to cause seizures, hemiplegia, and episodic ataxia.展开更多
Objective: To describe the clinical and pathologic features of a new dominantly inherited audiovestibular syndrome. Methods: History, examination, and audiometric testing in the proband, brother, and son; quantitative...Objective: To describe the clinical and pathologic features of a new dominantly inherited audiovestibular syndrome. Methods: History, examination, and audiometric testing in the proband, brother, and son; quantitative rotational testing in the proband and son; histopathology of the cochlea and vestibular labyrinth in the proband; sequencing candidate genes COCH and MYO7A in the brother and son. Results: Affected family members developed slowly progressive hearing loss beginning in their late 30s and progressive imbalance in their early 70s. Three of four affected had brief (minutes) episodes of vertigo typically occurring a few times per year. Auditory and vestibular function testing documented a slowly progressive loss of auditory and vestibular function. Postmortem examination showed a loss of hair cells in the cochlea and vestibular receptor organs. There were no cellular infiltrates or acidophilic deposits. No mutations were found in the COCH or MYO7A genes. Conclusions: This dominantly inherited audiovestibular syndrome results in a selective loss of hair cells in the auditory and vestibular end organs. Finding the causative gene could have important implications for understanding the pathophysiology of presbycusis and dysequilibrium of aging.展开更多
文摘Background: Transporters, ion pumps, and ion channels are membrane proteins that regulate selective permeability and maintain ionic gradients across cell membranes. Mutations in CACNA1A encoding a neuronal calcium channel and ATP1A2 encoding an ion pump cause episodic ataxia, hemiplegic migraine, and seizures. Mutant gene products of both CACNA1A and ATP1A2 may affect neurotransmission of glutamate, the most abundant excitatory amino acid neurotransmitter. Methods: We examined our patient population with episodic ataxia and hemiplegic migraine but with no mutation in either CACNA1A or ATP1A2. We looked for mutations in SLC1A3, which encodes the glutamate transporter excitatory amino acid transporter (EAAT) 1 that is important in removing glutamate from the synaptic cleft. Results: A patient with episodic ataxia, seizures, migraine, and alternating hemiplegia has a heterozygous mutation in SLC1A3 that is not present in his asymptomatic parents and controls. Expression studies of the mutant EAAT1 showed decreased expression of the protein with a markedly reduced capacity for glutamate uptake. When coexpressed, the mutant EAAT1 decreased the activity of wild-type EAAT1 but not of two other transporters EAAT2 or EAAT3, suggesting that mutant EAAT1 specifically multimerizes with wild-type EAAT1 to exert its dominant negative effect. Conclusion: Our data show that a heterozygous mutation in EAAT1 can lead to decreased glutamate uptake, which can contribute to neuronal hyperexcitability to cause seizures, hemiplegia, and episodic ataxia.
文摘Objective: To describe the clinical and pathologic features of a new dominantly inherited audiovestibular syndrome. Methods: History, examination, and audiometric testing in the proband, brother, and son; quantitative rotational testing in the proband and son; histopathology of the cochlea and vestibular labyrinth in the proband; sequencing candidate genes COCH and MYO7A in the brother and son. Results: Affected family members developed slowly progressive hearing loss beginning in their late 30s and progressive imbalance in their early 70s. Three of four affected had brief (minutes) episodes of vertigo typically occurring a few times per year. Auditory and vestibular function testing documented a slowly progressive loss of auditory and vestibular function. Postmortem examination showed a loss of hair cells in the cochlea and vestibular receptor organs. There were no cellular infiltrates or acidophilic deposits. No mutations were found in the COCH or MYO7A genes. Conclusions: This dominantly inherited audiovestibular syndrome results in a selective loss of hair cells in the auditory and vestibular end organs. Finding the causative gene could have important implications for understanding the pathophysiology of presbycusis and dysequilibrium of aging.
