Molecular studies of familial adult myoclonic epilepsy and Andersen's syndrome

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Publication Type dissertation
School or College School of Medicine
Department Human Genetics
Author Plaster, Nikki Marie
Title Molecular studies of familial adult myoclonic epilepsy and Andersen's syndrome
Date 2001-12
Description We investigated two electrical episodic disorder, familial adult myoclonic epilepsy (FAME) and Andersen's syndrome (AS), to identify molecular components involved in cell excitability in humans. FAME is characterized by autosomal dominant inheritance, adult onset, myoclonus of the limbs, generalized tonic-clonic seizures, and benign course. We examine nine Japanese families exhibiting FAME. A genome-wide screen performed on four families identified a FAME locus on chromosome 8q24. Physical and fine mapping of the locus further restricted the gene to a 700 kilobase region. This region contains four putative genes, EIF3S3, hHR21(sp), ZnT-5, and AA913447. Although none of these genes can currently be eliminated as candidates for the FAME gene EIF3S3, ZnT-5, and hHR21(sp) are unlikely to be responsible for the FAME phenotype due to either their location or the absence of coding mutations. Complete sequence of AA913447 has not yet been identified and is currently under investigation. Mutational analysis of this putative gene and possible other unidentified genes in the FAME locus will lead to the identification of the FAME gene. As is characterized by autosomal dominant inheritance of cardiac manifestations (including cardiac arrhythmia and long QT syndrome), periodic paralysis, and facial and skeletal dysmorphology. We examined 23 families exhibiting the characteristic traits of AS. A genome-wide screen localized an AS gene to chromosome 17q23. Mutational analysis identified 12 different mutations in the inwardly rectifying K+ channel subunit Kir2.1 that segregate with the disorder in 16 families. Electrophysiological examination of two mutant subunits demonstrated a loss of function and a dominant negative effect of Kir2.1. Investigation of sub cellular localization in five mutant subunits demonstrated their mutation in Kir2.1 cause the characteristics traits of AS, and that this is accomplished (in the case of some mutations) by disrupting channel function at the plasma membrane. The results of these studies revealed novel associations between cardiac and skeletal muscle membrane excitability, and developmental signaling. Further investigation of FAME, AS, and there responsible gene products is expected to enrich the current understanding of cell excitability in the brain, heart, and skeletal muscle.
Type Text
Publisher University of Utah
Subject Epilepsy - Genetic aspects; Genetic disorders
Subject MESH Epilepsies, Myoclonic; Glycogen Storage Disease Type IV; Genetic Diseases, Inborn
Dissertation Institution University of Utah
Dissertation Name PhD
Language eng
Relation is Version of Digital reproduction of "Molecular studies of familial adult myoclonic epilepsy and Andersen's syndrome". Spencer S. Eccles Health Sciences Library.
Rights Management © Nikki Marie Plaster
Format Medium application/pdf
Format Extent 2,100,049 bytes
Identifier undthes,4235
Source Original: University of Utah Spencer S. Eccles Health Sciences Library (no longer available)
Master File Extent 2,100,131 bytes
ARK ark:/87278/s6ws8w43
Setname ir_etd
ID 191699
Reference URL https://collections.lib.utah.edu/ark:/87278/s6ws8w43
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