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Subunits of the translation initiation factor eIF2B are mutant in leukoencephalopathy with vanishing white matter. 总被引:10,自引:0,他引:10
P A Leegwater G Vermeulen A A K?nst S Naidu J Mulders A Visser P Kersbergen D Mobach D Fonds C G van Berkel R J Lemmers R R Frants C B Oudejans R B Schutgens J C Pronk M S van der Knaap 《Nature genetics》2001,29(4):383-388
Leukoencephalopathy with vanishing white matter (VWM) is an inherited brain disease that occurs mainly in children. The course is chronic-progressive with additional episodes of rapid deterioration following febrile infection or minor head trauma. We have identified mutations in EIF2B5 and EIF2B2, encoding the epsilon- and beta-subunits of the translation initiation factor eIF2B and located on chromosomes 3q27 and 14q24, respectively, as causing VWM. We found 16 different mutations in EIF2B5 in 29 patients from 23 families. We also found two distantly related individuals who were homozygous with respect to a missense mutation in EIF2B2, affecting a conserved amino acid. Three other patients also had mutations in EIF2B2. As eIF2B has an essential role in the regulation of translation under different conditions, including stress, this may explain the rapid deterioration of people with VWM under stress. Mutant translation initiation factors have not previously been implicated in disease. 相似文献
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van Overveld PG Lemmers RJ Sandkuijl LA Enthoven L Winokur ST Bakels F Padberg GW van Ommen GJ Frants RR van der Maarel SM 《Nature genetics》2003,35(4):315-317
The autosomal dominant myopathy facioscapulohumeral muscular dystrophy (FSHD1, OMIM 158900) is caused by contraction of the D4Z4 repeat array on 4qter. We show that this contraction causes marked hypomethylation of the contracted D4Z4 allele in individuals with FSHD1. Individuals with phenotypic FSHD1, who are clinically identical to FSHD1 but have an unaltered D4Z4, also have hypomethylation of D4Z4. These results strongly suggest that hypomethylation of D4Z4 is a key event in the cascade of epigenetic events causing FSHD1. 相似文献
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Facioscapulohumeral muscular dystrophy is uniquely associated with one of the two variants of the 4q subtelomere 总被引:12,自引:0,他引:12
Lemmers RJ de Kievit P Sandkuijl L Padberg GW van Ommen GJ Frants RR van der Maarel SM 《Nature genetics》2002,32(2):235-236
Contractions in the polymorphic D4Z4 repeat array of subtelomere 4qter cause autosomal dominant facioscapulohumeral muscular dystrophy in humans. A polymorphic segment of 10 kb directly distal to D4Z4 exists in two allelic forms, 4qA and 4qB. Although both alleles are equally common in the general population, we now report that FSHD is associated solely with the 4qA allele. 相似文献
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Freilinger T Anttila V de Vries B Malik R Kallela M Terwindt GM Pozo-Rosich P Winsvold B Nyholt DR van Oosterhout WP Artto V Todt U Hämäläinen E Fernández-Morales J Louter MA Kaunisto MA Schoenen J Raitakari O Lehtimäki T Vila-Pueyo M Göbel H Wichmann E Sintas C Uitterlinden AG Hofman A Rivadeneira F Heinze A Tronvik E van Duijn CM Kaprio J Cormand B Wessman M Frants RR Meitinger T Müller-Myhsok B Zwart JA Färkkilä M Macaya A Ferrari MD Kubisch C Palotie A Dichgans M 《Nature genetics》2012,44(7):777-782
Migraine without aura is the most common form of migraine, characterized by recurrent disabling headache and associated autonomic symptoms. To identify common genetic variants associated with this migraine type, we analyzed genome-wide association data of 2,326 clinic-based German and Dutch individuals with migraine without aura and 4,580 population-matched controls. We selected SNPs from 12 loci with 2 or more SNPs associated with P values of <1 × 10(-5) for replication testing in 2,508 individuals with migraine without aura and 2,652 controls. SNPs at two of these loci showed convincing replication: at 1q22 (in MEF2D; replication P = 4.9 × 10(-4); combined P = 7.06 × 10(-11)) and at 3p24 (near TGFBR2; replication P = 1.0 × 10(-4); combined P = 1.17 × 10(-9)). In addition, SNPs at the PHACTR1 and ASTN2 loci showed suggestive evidence of replication (P = 0.01; combined P = 3.20 × 10(-8) and P = 0.02; combined P = 3.86 × 10(-8), respectively). We also replicated associations at two previously reported migraine loci in or near TRPM8 and LRP1. This study identifies the first susceptibility loci for migraine without aura, thereby expanding our knowledge of this debilitating neurological disorder. 相似文献
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Richards A van den Maagdenberg AM Jen JC Kavanagh D Bertram P Spitzer D Liszewski MK Barilla-Labarca ML Terwindt GM Kasai Y McLellan M Grand MG Vanmolkot KR de Vries B Wan J Kane MJ Mamsa H Schäfer R Stam AH Haan J de Jong PT Storimans CW van Schooneveld MJ Oosterhuis JA Gschwendter A Dichgans M Kotschet KE Hodgkinson S Hardy TA Delatycki MB Hajj-Ali RA Kothari PH Nelson SF Frants RR Baloh RW Ferrari MD Atkinson JP 《Nature genetics》2007,39(9):1068-1070
Autosomal dominant retinal vasculopathy with cerebral leukodystrophy is a microvascular endotheliopathy with middle-age onset. In nine families, we identified heterozygous C-terminal frameshift mutations in TREX1, which encodes a 3'-5' exonuclease. These truncated proteins retain exonuclease activity but lose normal perinuclear localization. These data have implications for the maintenance of vascular integrity in the degenerative cerebral microangiopathies leading to stroke and dementias. 相似文献
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