Miriam H. Meisler
University of Michigan
TransgeneGeneGene mappingInternal medicineEndocrinologyMutantMolecular biologyNeuroscienceAmylaseAlleleEpilepsyExonMutationSodium channelGeneticsMedicineMissense mutationLocus (genetics)BiologyCell biology
211Publications
66H-index
14.2kCitations
Publications 212
Newest
#1Ian C. Wenker (University of Virginia Health System)H-Index: 2
#2Frida A. Teran (UI: University of Iowa)H-Index: 3
Last. Manoj K. Patel (University of Virginia Health System)H-Index: 24
view all 12 authors...
OBJECTIVE Sudden unexpected death in epilepsy (SUDEP) is an unpredictable and devastating comorbidity of epilepsy that is believed to be due to cardiorespiratory failure immediately after generalized convulsive seizures. METHODS We performed cardiorespiratory monitoring of seizure-induced death in mice carrying either an p.Arg1872Trp or p.Asn1768Asp mutation in a single Scn8a allele - mutations identified from patients that died from SUDEP - and by seizure-induced death of pentylenetetrazole-tre...
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#1Wenxi Yu (UM: University of Michigan)H-Index: 2
#2Corrine E Smolen (UM: University of Michigan)H-Index: 1
Last. Miriam H. Meisler (UM: University of Michigan)H-Index: 66
view all 4 authors...
De novo mutations of neuronal sodium channels are responsible for approximately 5% of developmental and epileptic encephalopathies, but the role of somatic mutation of these genes in adult-onset epilepsy is not known. We evaluated the role of post-zygotic somatic mutation by adult activation of a conditional allele of the pathogenic variant Scn8aR1872W in the mouse. After activation of CAG-CRE-ER by tamoxifen, the mutant transcript was expressed throughout the brain at a level proportional to ta...
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#1Miriam H. Meisler (UM: University of Michigan)H-Index: 66
#2Sophie F Hill (UM: University of Michigan)H-Index: 4
Last. Wenxi Yu (UM: University of Michigan)H-Index: 2
view all 3 authors...
Source
#1Miriam H. Meisler (UM: University of Michigan)H-Index: 66
#2Sophie F Hill (UM: University of Michigan)H-Index: 4
Last. Wenxi Yu (UM: University of Michigan)H-Index: 2
view all 3 authors...
The voltage-gated sodium channel α-subunit genes comprise a highly conserved gene family. Mutations of three of these genes, SCN1A, SCN2A and SCN8A, are responsible for a significant burden of neurological disease. Recent progress in identification and functional characterization of patient variants is generating new insights and novel approaches to therapy for these devastating disorders. Here we review the basic elements of sodium channel function that are used to characterize patient variants...
2 CitationsSource
#1Wenxi Yu (UM: University of Michigan)H-Index: 2
#2Sophie F Hill (UM: University of Michigan)H-Index: 4
Last. Miriam H. Meisler (UM: University of Michigan)H-Index: 66
view all 6 authors...
Objective SCN8A encephalopathy is a developmental epileptic encephalopathy typically caused by de novo gain-of-function mutations in Nav 1.6. Severely affected individuals exhibit refractory seizures, developmental delay, cognitive disabilities, movement disorders, and elevated risk of sudden death. Patients with the identical SCN8A variant can differ in clinical course, suggesting a role for modifier genes in determining disease severity. The identification of genetic modifiers contributes to u...
4 CitationsSource
#1Guy M. Lenk (UM: University of Michigan)H-Index: 23
#2Paymaan Jafar-NejadH-Index: 17
Last. Miriam H. MeislerH-Index: 66
view all 14 authors...
OBJECTIVE: SCN8A encephalopathy is a developmental and epileptic encephalopathy (DEE) caused by de novo gain-of-function mutations of sodium channel Nav 1.6 that result in neuronal hyperactivity. Affected individuals exhibit early onset drug-resistant seizures, developmental delay, and cognitive impairment. This study was carried out to determine whether reducing the abundance of the Scn8a transcript with an antisense oligonucleotide (ASO) would delay seizure onset and prolong survival in a mous...
12 CitationsSource
#1Juanjiangmeng Du (University of Cologne)H-Index: 5
#2Sean K. Simmons (Broad Institute)H-Index: 1
Last. Dennis LalH-Index: 25
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Abstract The four voltage-gated sodium channels SCN1/2/3/8A have been associated with heterogeneous types of developmental disorders, each presenting with disease specific temporal and cell type specific gene expression. Using single-cell RNA sequencing transcriptomic data from humans and mice, we observe that SCN1A is predominantly expressed in inhibitory neurons. In contrast, SCN2/3/8A are profoundly expressed in excitatory neurons with SCN2/3A starting prenatally, followed by SCN1/8A neonatal...
3 CitationsSource
#1Miriam H. Meisler (UM: University of Michigan)H-Index: 66
De novo mutations of the neuronal sodium channel SCN8A have been identified in approximately 2% of individuals with epileptic encephalopathy. These missense mutations alter the biophysical properties of sodium channel Nav1.6 in ways that lead to neuronal hyperexcitability. We generated two mouse models carrying patient mutations N1768D and R1872W to examine the effects on neuronal function in vivo. The conditional R1872W mutation is activated by expression of CRE recombinase, permitting characte...
9 CitationsSource
#1Eric R. Wengert (UVA: University of Virginia)H-Index: 5
Last. Rikke S. Møller (University of Southern Denmark)H-Index: 52
view all 17 authors...
OBJECTIVE: Monoallelic de novo gain-of-function variants in the voltage-gated sodium channel SCN8A are one of the recurrent causes of severe developmental and epileptic encephalopathy (DEE). In addition, a small number of de novo or inherited monoallelic loss-of-function variants have been found in patients with intellectual disability, autism spectrum disorder, or movement disorders. Inherited monoallelic variants causing either gain or loss-of-function are also associated with less severe cond...
9 CitationsSource
#1Guy M. Lenk (UM: University of Michigan)H-Index: 23
#2Young Nam Park (UM: University of Michigan)H-Index: 5
Last. Jacob O. Kitzman (UM: University of Michigan)H-Index: 36
view all 11 authors...
Defective biosynthesis of the phospholipid PI(3,5)P2 underlies neurological disorders characterized by cytoplasmic accumulation of large lysosome-derived vacuoles. To identify novel genetic causes of lysosomal vacuolization, we developed an assay for enlargement of the lysosome compartment that is amenable to cell sorting and pooled screens. We first demonstrated that the enlarged vacuoles that accumulate in fibroblasts lacking FIG4, a PI(3,5)P2 biosynthetic factor, have a hyperacidic pH compare...
7 CitationsSource