Sun, Moon, Stars, Rain, Vol. 7 No. 11

Official publication of the Sigma Tau Delta English Honor Society, Alpha Zet Chapter, Stephen F. Austin State University. Published one a year in the Fall Semester, in cooperation with the English Department of Stephen F. Austin State University.https://scholarworks.sfasu.edu/smsr/1000/thumbnail.jp

Sun, Moon, Stars, Rain, Vol. 7 No. 11

Official publication of the Sigma Tau Delta English Honor Society, Alpha Zet Chapter, Stephen F. Austin State University. Published one a year in the Fall Semester, in cooperation with the English Department of Stephen F. Austin State University

Intronic ATTTC repeat expansions in STARD7 in familial adult myoclonic epilepsy linked to chromosome 2

Familial Adult Myoclonic Epilepsy (FAME) is characterised by cortical myoclonic tremor usually from the second decade of life and overt myoclonic or generalised tonic-clonic seizures. Four independent loci have been implicated in FAME on chromosomes (chr) 2, 3, 5 and 8. Using whole genome sequencing and repeat primed PCR, we provide evidence that chr2-linked FAME (FAME2) is caused by an expansion of an ATTTC pentamer within the first intron of STARD7. The ATTTC expansions segregate in 158/158 individuals typically affected by FAME from 22 pedigrees including 16 previously reported families recruited worldwide. RNA sequencing from patient derived fibroblasts shows no accumulation of the AUUUU or AUUUC repeat sequences and STARD7 gene expression is not affected. These data, in combination with other genes bearing similar mutations that have been implicated in FAME, suggest ATTTC expansions may cause this disorder, irrespective of the genomic locus involvedSupplementary Information: Supplementary Data 1; Supplementary Data 2; Reporting Summary.NHMRC; Women’s and Children’s Hospital Research Foundation; Muir Maxwell Trust; Epilepsy Society; The European Fund for Regional Development; The province of Friesland, Dystonia Medical Research Foundation; Stichting Wetenschapsfonds Dystonie Vereniging; Fonds Psychische Gezondheid; Phelps Stichting; The Italian Ministry of Health; Istituto Superiore di Sanità, Italy; Undiagnosed Disease Network Italy; The Fondation maladies rares, University Hospital Essen and UK Department of Health’s NIHR.https://www.nature.com/ncommspm2020Neurolog

Mutations in DEPDC5 cause Familial Focal Epilepsy with Variable Foci and are a common cause of familial non-lesional focal epilepsy

OBJECTIVE: To identify the genetic cause of autosomal dominant Familial Focal Epilepsy with Variable Foci (FFEVF), to investigate the prevalence of mutations in the FFEVF causative gene in familial cases of non-lesional focal epilepsy, to study the expression in the brain and the subcellular localization of the encoded protein. BACKGROUND: FFEVF is characterized by seizures arising from different cortical regions in different affected family members. Brain imaging is normal. Seizure onset varies from infancy to adult life. Affected individuals occasionally have neuropsychiatric co-morbidities. Linkage studies mapped FFEVF to chromosome 22q12, but the causative gene had so far eluded identification. DESIGN/METHODS: We applied exome sequencing to two FFEVF families previously linked to chromosome 22q12, identifying DEPDC5 as the most likely candidate gene. We sequenced DEPDC5 in six additional 22q12-linked families and scanned DEPDC5 for sequence variation in 82 unrelated probands from families with at least two individuals with non-lesional focal epilepsy. We used qRT-PCR, immunofluorescence and western blot analysis to study DEPDC5 expression and subcellular localization. RESULTS: Heterozygous mutations in DEPDC5 were identified in 7/8 FFEVF families linked to chromosome 22q12 and in 10/82 (12.2%) probands from the small families with focal epilepsy. Each DEPDC5 mutation segregated with the FFEVF phenotype in the respective family and was absent in both dbSNP135 and an in-house exome sequencing database of 710 chromosomes. Most mutations caused premature termination codons suggesting haploinsufficiency as pathogenic mechanism. DEPDC5 encodes a1604 amino acid protein of unknown function, probably implicated in modulation of intracellular signaling.Mouse Depdc5 transcripts were detected at low levels in all brain regions and throughout brain development. Immunofluorescence analyses in mouse and human brain showed specific expression in neurons and perinuclear localization. CONCLUSIONS: Our findings establish DEPDC5 mutations as the most common known cause of familial focal epilepsy and identify a novel pathogenic pathway for epilepsy

Mutations in DEPDC5 cause familial focal epilepsy with variable foci

<p>The majority of epilepsies are focal in origin, with seizures emanating from one brain region. Although focal epilepsies often arise from structural brain lesions, many affected individuals have normal brain imaging. The etiology is unknown in the majority of individuals, although genetic factors are increasingly recognized. Autosomal dominant familial focal epilepsy with variable foci (FFEVF) is notable because family members have seizures originating from different cortical regions(1). Using exome sequencing, we detected DEPDC5 mutations in two affected families. We subsequently identified mutations in five of six additional published large families with FFEVF. Study of families with focal epilepsy that were too small for conventional clinical diagnosis with FFEVF identified DEPDC5 mutations in approximately 12% of families (10/82). This high frequency establishes DEPDC5 mutations as a common cause of familial focal epilepsies. Shared homology with G protein signaling molecules and localization in human neurons suggest a role of DEPDC5 in neuronal signal transduction.</p>

Intronic ATTTC repeat expansions in STARD7 in familial adult myoclonic epilepsy linked to chromosome 2

Familial Adult Myoclonic Epilepsy (FAME) is characterised by cortical myoclonic tremor usually from the second decade of life and overt myoclonic or generalised tonic-clonic seizures. Four independent loci have been implicated in FAME on chromosomes (chr) 2, 3, 5 and 8. Using whole genome sequencing and repeat primed PCR, we provide evidence that chr2-linked FAME (FAME2) is caused by an expansion of an ATTTC pentamer within the first intron of STARD7. The ATTTC expansions segregate in 158/158 individuals typically affected by FAME from 22 pedigrees including 16 previously reported families recruited worldwide. RNA sequencing from patient derived fibroblasts shows no accumulation of the AUUUU or AUUUC repeat sequences and STARD7 gene expression is not affected. These data, in combination with other genes bearing similar mutations that have been implicated in FAME, suggest ATTTC expansions may cause this disorder, irrespective of the genomic locus involved