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Variants in triggering receptor expressed on myeloid cells 2 are associated with both behavioral variant frontotemporal lobar degeneration and Alzheimer's disease

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NEUROBIOLOGY OF AGING 2013年第8期34卷 2077.e11-2077.e18页

作者： Giraldo, Margarita Lopera, Francisco Siniard, Ashley L. Corneveaux, Jason J. schrauwen, isabelle Carvajal, Julian Munoz, Claudia Ramirez-Restrepo, Manuel Gaiteri, Chris Myers, Amanda J. Caselli, Richard J. Kosik, Kenneth S. Reiman, Eric M. Huentelman, Matthew J. Translat Genom Res Inst TGen Neurogen Div Phoenix AZ 85004 USA Arizona Alzheimers Consortium Phoenix AZ USA Banner Alzheimers Inst Phoenix AZ USA Univ Antwerp Dept Med Genet B-2020 Antwerp Belgium Mayo Clin Dept Neurol Scottsdale AZ USA Univ Calif Santa Barbara Neurosci Res Inst Dept Mol Cellular & Dev Biol Santa Barbara CA 93106 USA Univ Antioquia Grp Neurociencias Antioquia Medellin Colombia Inst Neurol Colombia Medellin Colombia Univ Miami Miller Sch Med Dept Psychiat & Behav Sci Miami FL 33136 USA Univ Miami Miller Sch Med Div Neurosci Miami FL 33136 USA Univ Miami Miller Sch Med Dept Human Genet & Genom Miami FL 33136 USA Univ Miami Miller Sch Med Ctr Aging Miami FL 33136 USA Sage Bionetworks Seattle WA USA

Recent evidence suggests that rare genetic variants within the TREM2 gene are associated with increased risk of Alzheimer's disease. TREM2 mutations are the genetic basis for a condition characterized by polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL) and an early-onset dementia syndrome. TREM2 is important in the phagocytosis of apoptotic neuronal cells by microglia in the brain. Loss of function might lead to an impaired clearance and to accumulation of necrotic debris and subsequent neurodegeneration. In this study, we investigated a consanguineous family segregating autosomal recessive behavioral variant FTLD from Antioquia, Colombia. Exome sequencing identified a nonsense mutation in TREM2 (***198X) segregating with disease. Next, using a cohort of clinically characterized and neuropathologically verified sporadic AD cases and controls, we report replication of the AD risk association at rs75932628 within TREM2 and demonstrate that TREM2 is significantly overexpressed in the brain tissue from AD cases. These data suggest that a mutational burden in TREM2 may serve as a risk factor for neurodegenerative disease in general, and that potentially this class of TREM2 variant carriers with dementia should be considered as having a molecularly distinct form of neurodegenerative disease. (c) 2013 Elsevier Inc. All rights reserved.

关键词： TREM2 Alzheimer's disease FTLD neurodegeneration

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COL1A1 association and otosclerosis: A meta-analysis

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AMERICAN JOURNAL OF MEDICAL GENETICS PART A 2012年第5期158A卷 1066-1070页

作者： schrauwen, isabelle Khalfallah, Ayda Ealy, Megan Fransen, Erik Claes, Charlotte Huber, Alex Murillo, Laura Rodriguez Masmoudi, Saber Smith, Richard J. H. Van Camp, Guy Univ Antwerp Dept Med Genet B-2610 Antwerp Belgium Univ Sfax Equipe Procedes Criblages Mol & Cellulaires Lab Microorganismes & Biomol Ctr Biotechnol Sfax Sfax Tunisia Univ Iowa Dept Otolaryngol Mol Otolaryngol Res Labs Iowa City IA USA Univ Antwerp StatUa Ctr Stat B-2020 Antwerp Belgium Univ Zurich Hosp Dept Otorhinolaryngol Head & Neck Surg CH-8091 Zurich Switzerland Columbia Univ Dept Psychiat Med Ctr New York NY USA

Otosclerosis is a disease of abnormal bone remodeling in the human otic capsule that can lead to progressive hearing loss. Little of the underlying disease etiology has been elucidated thus far, although several studies have suggested that COL1A1 may play a role based on its importance in bone metabolism and other diseases like osteoporosis and osteogenesis imperfecta. Genetic association studies between COL1A1 and otosclerosis, however, have been contradictory. To resolve this issue, we studied a large Belgian-Dutch and a Swiss population for a genetic association between COL1A1 and otosclerosis and additionally performed a meta-analysis to investigate the overall genetic effect of COL1A1 on all otosclerosis populations studied to date. We found a significant association both in the Belgian-Dutch population and in the meta-analysis. In aggregate, our analysis supports evidence for an association between COL1A1 and otosclerosis although effect sizes of the variants reported in the initial studies are likely to be an overestimate of true effect sizes. (c) 2012 Wiley Periodicals, Inc.

关键词： COL1A1 otosclerosis meta-analysis

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A Mutation in CABP2, Expressed in Cochlear Hair Cells, Causes Autosomal-Recessive Hearing Impairment

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AMERICAN JOURNAL OF HUMAN GENETICS 2012年第4期91卷 636-645页

作者： schrauwen, isabelle Helfmann, Sarah Inagaki, Akira Predoehl, Friederike Tabatabaiefar, Mohammad Amin Picher, Maria Magdalena Sommen, Manou Seco, Celia Zazo Oostrik, Jaap Kremer, Hannie Dheedene, Annelies Claes, Charlotte Fransen, Erik Chaleshtori, Morteza Hashemzadeh Coucke, Paul Lee, Amy Moser, Tobias Van Camp, Guy Univ Gottingen Sch Med Dept Otolaryngol Collaborat Res Ctr 889InnerEar Lab D-37075 Gottingen Germany Univ Antwerp Dept Med Genet B-2610 Antwerp Belgium Univ Iowa Dept Mol Physiol & Biophys Iowa City IA 52242 USA Univ Iowa Dept Otolaryngol Head & Neck Surg Iowa City IA 52242 USA Univ Iowa Dept Neurol Iowa City IA 52242 USA Ahvaz Jundishapour Univ Med Sci Sch Med Dept Med Genet Ahvaz *** Iran Shahrekord Univ Med Sci Sch Med Cellular & Mol Res Ctr Shahrekord 88155137 Iran Radboud Univ Nijmegen Med Ctr Dept Otorhinolaryngol NL-6500 HB Nijmegen Netherlands Radboud Univ Nijmegen Med Ctr Donders Inst Brain Cognit & Behav NL-6500 HB Nijmegen Netherlands Radboud Univ Nijmegen Med Ctr Nijmegen Ctr Mol Life Sci NL-6500 HB Nijmegen Netherlands Radboud Univ Nijmegen Med Ctr Dept Human Genet NL-6500 HB Nijmegen Netherlands Univ Ghent Ctr Med Genet B-9000 Ghent Belgium

CaBPs are a family of Ca2+-binding proteins related to calmodulin and are localized in the brain and sensory organs, including the retina and cochlea. Although their physiological roles are not yet fully elucidated, CaBPs modulate Ca2+ signaling through effectors such as voltage-gated Ca-v Ca2+ channels. In this study, we identified a splice-site mutation (c.637+1G>T) in Ca2+-binding protein 2 (CABP2) in three consanguineous Iranian families affected by moderate-to-severe hearing loss. This mutation, most likely a founder mutation, probably leads to skipping of exon 6 and premature truncation of the protein (***164Serfs(star)4). Compared with wild-type CaBP2, the truncated CaBP2 showed altered Ca2+ binding in isothermal titration calorimetry and less potent regulation of Ca(v)1.3 Ca2+ channels. We show that genetic defects in CABP2 cause moderate-to-severe sensorineural hearing impairment. The mutation might cause a hypofunctional CaBP2 defective in Ca2+ sensing and effector regulation in the inner ear.

关键词： MUTATION (Biology) CALCIUM channels HAIR cells GENE expression GENETIC disorders HEARING disorders CARRIER proteins

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Commentary on "Otosclerosis: Thirty-Year Follow-Up After Surgery"

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ANNALS OF OTOLOGY RHINOLOGY AND LARYNGOLOGY 2011年第9期120卷 615-616页

作者： Ealy, Megan schrauwen, isabelle Van Camp, Guy Univ Iowa Mol Otolaryngol Res Labs Iowa City IA 52242 USA Univ Antwerp Dept Med Genet B-2020 Antwerp Belgium

In this article the authors reflect on the article 'Otosclerosis: Thirty-Year Follow-Up After Surgery,' by Ylva Dahlin Redfors and Claes Möller. They are supportive of the research which is contained in the article and suggest that the results of the research highlight the need for genetic studies to elucidate the causes of otosclerosis.

关键词： EAR ossicles SURGERY DEAFNESS OTOSCLEROSIS OUTCOME assessment (Medical care) TREATMENT effectiveness EVALUATION

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A 1 bp Deletion in the Dual Reading Frame Deafness Gene LRTOMT Causes a Frameshift From the First Into the Second Reading Frame

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AMERICAN JOURNAL OF MEDICAL GENETICS PART A 2011年第8期155A卷 2021-2023页

作者： Vanwesemael, Maarten schrauwen, isabelle Ceuppens, Ruben Alasti, Fatemeh Jorssen, Ellen Farrokhi, Effat Chaleshtori, Morteza Hashemzadeh Van Camp, Guy Univ Antwerp Dept Med Genet B-2610 Antwerp Belgium Shahrekord Univ Med Sci Sch Med Cellular & Mol Res Ctr Shahrekord Iran

Congenital hearing impairment (HI) affects one in 650 newborns and has a genetic cause in 50% of the cases. Autosomal recessive non-syndromic hearing impairment (ARNSHI) is responsible for 70-80% of all hereditary cases of HI. ARNSHI is genetically highly heterogeneous and until today mutations in 37 genes have been identified [Van Camp and Smith, 2011 ]. One of the latest genes for ARNSHI is LRTOMT (at locus DFNB63 on Ilql3.3-ql3.4). The structure of human LRTOMT has only recently been elucidated [Ahmed et al, 2008]. LRTOMT is an evolutionary recent fusion gene with alternative reading frames that exclusively exists in primates and is a fusion of non-primate Lrrc51 (Leucine rich repeat containing 51) and Tomt (Transmembrane O-methyltransferase) sequences. Human LRTOMThzs ten exons, of which the first two are non-coding. Five transcripts are known and it has two different major protein products, LRTOMT1 and LRTOMT2. Both proteins contain a predicted transmembrane domain, located in exon 5 of LRTOMT1 and in exon 8 of LRTOMT2. LRTOMT2 is also described as COMT2 (Catechol-O-methyltransferase) [Du et al., 2008].

关键词： Hearing Disorders Gene Fusion Frameshift Mutation LRTOMT gene Transmembrane domains Reading Frames Exons Deafness Primates

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Association of COL1A1 and TGFB1 Polymorphisms with Otosclerosis in a Tunisian Population

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ANNALS OF HUMAN GENETICS 2011年第5期75卷 598-604页

作者： Khalfallah, Ayda schrauwen, isabelle Mnejja, Malek HadjKacem, Hassen Dhouib, Leila Mosrati, Mohamed Ali Hakim, Bochra Lahmar, Imed Charfeddine, Ilhem Driss, Nabil Ayadi, Hammadi Ghorbel, Abdelmonem Van Camp, Guy Masmoudi, Saber Univ Sfax Ctr Biotechnol Sfax Equipe Procedes Criblages Mol & Cellulaires Lab Microorganismes & Biomol Sfax Tunisia Univ Antwerp Dept Med Genet B-2610 Antwerp Belgium CHUH Bourguiba Sfax Serv ORL Sfax Tunisia CHU Mahdia Serv ORL Mahdia Tunisia

Otosclerosis is a condition characterized by an abnormal bone metabolism in the otic capsule, resulting in conductive and/or sensorineural hearing loss. Otosclerosis is a common disorder in which genes play an important role. Case-control association studies have implicated several genes in the abnormal bone metabolism associated with otosclerosis: COL1A1, TGFB1, BMP2, and BMP4. To investigate the association of these genes with otosclerosis in the Tunisian population, we examined nine single nucleotide polymorphisms (SNPs) in 159 unrelated otosclerosis patients and 155 unrelated controls. We found an association of rs11327935 in COL1A1 with otosclerosis that was shown to be sex specific. The coding polymorphism T263I in TGFB1 was also associated with otosclerosis in the Tunisian population. The effect sizes of both the associations were consistent with previous studies, as the same effect was found in all cases. The association of BMP2 and BMP4 was not significant. However, a trend towards association was found for the BMP4 gene that was consistent with earlier reports. In conclusion, this study replicates and strengthens the evidence for association between polymorphisms of COL1A1 and TGFB1 in the genetic aetiology of otosclerosis.

关键词： Meta-analysis genetic otosclerosis case-control study

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The Etiology of Otosclerosis: A Combination of Genes and Environment

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LARYNGOSCOPE 2010年第6期120卷 1195-1202页

作者： schrauwen, isabelle Van Camp, Guy Univ Antwerp Dept Med Genet B-2610 Antwerp Belgium

Otosclerosis is a common form of hearing loss characterized by abnormal bone remodeling in the otic capsule. It is a complex genetic disease, caused by a combination of genetic and environmental factors. During the past decade, several attempts have been made to identify factors for otosclerosis. This review provides an overview of the current understanding of the etiology of otosclerosis and describes the genetic and environmental factors that have been implicated in the disease. Environmental factors include fluoride and viral factors, particularly measles. Genetic association studies for otosclerosis have reported several associations of genetic variants that influence the risk of disease, mainly involving bone remodeling pathways, although their individual risk contributions are small. Rare inonogenic forms of otosclerosis also exist, which are caused by a mutation in a single gene leading to a clear familial segregation of the disease. Linkage analysis of large otosclerosis families has led to the identification of seven loci, and recently evidence was found that T cell receptor beta is a gene responsible for familial otosclerosis, suggesting an underlying immunological pathway. However, this might also represent an autoimmune process, a hypothesis that is supported by other data as well. In conclusion, a variety of pathways have been identified to be involved in the development of otosclerosis, showing that distinct mechanisms involving both genetic and environmental risk factors can influence and contribute to a similar disease outcome.

关键词： Otosclerosis genetics complex disease

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Phenotype of the First Otosclerosis Family Linked to OTSC10

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LARYNGOSCOPE 2011年第4期121卷 838-845页

作者： Weegerink, Nicole J. D. schrauwen, isabelle Huygen, Patrick L. M. Pennings, Ronald J. E. Cremers, Cor W. R. J. Van Camp, Guy Kunst, Henricus P. M. Radboud Univ Nijmegen Med Ctr Donders Ctr Brain Cognit & Behav Dept Otorhinolaryngol NL-6500 HB Nijmegen Netherlands Univ Antwerp Dept Med Genet B-2020 Antwerp Belgium

Objectives: To report on the audiometric findings in the first otosclerosis family linked to OTSC10. Study Design: Retrospective cohort study. Methods: A family study in a large otosclerosis family was performed, and a pedigree was constructed. Examination of all family members consisted of medical history guided by a questionnaire, pure-tone audiometry, otoscopy, and collection of blood samples for genetic linkage analysis. In addition, a selected group underwent stapedial reflex measurements and tympanometry. Cross-sectional as well as longitudinal analyses of audiometric data were performed. Results: Eleven family members were identified as clinically affected and were all carriers of the disease haplotype. Twelve clinically unaffected family members carried the disease haplotype as well. Cross-sectional analyses of clinically affected family members showed no significant progression of air conduction (AC) thresholds, bone conduction (BC) thresholds, and air-bone gap (ABG) levels with increasing age. Longitudinal regression analyses in one family member revealed significant deterioration of AC thresholds at all frequencies. The BC thresholds showed a significant increase with advancing age at 0.5 kHz, 2 kHz, and 4 kHz. A significant progression of ABG was seen at 8 kHz. Conclusions: The intersubject variation, in terms of age of onset, level of progression, and audiogram configuration, was remarkable, probably due to reduced penetrance and variable expression of the disease. Long-term audiometric data in one patient, however, were useful to demonstrate progression of hearing impairment.

关键词： Otosclerosis OTSC10 phenotype

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DFNA8/12 Caused by TECTA Mutations is the Most Identified Subtype of Nonsyndromic Autosomal Dominant Hearing Loss

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HUMAN MUTATION 2011年第7期32卷 825-834页

作者： Hildebrand, Michael S. Morin, Matias Meyer, Nicole C. Mayo, Fernando Modamio-Hoybjor, Silvia Mencia, Angeles Olavarrieta, Leticia Morales-Angulo, Carmelo Nishimura, Carla J. Workman, Heather DeLuca, Adam P. del Castillo, Ignacio Taylor, Kyle R. Tompkins, Bruce Goodman, Corey W. schrauwen, isabelle Van Wesemael, Maarten Lachlan, K. Shearer, A. Eliot Braun, Terry A. Huygen, Patrick L. M. Kremer, Hannie Van Camp, Guy Moreno, Felipe Casavant, Thomas L. Smith, Richard J. H. Moreno-Pelayo, Miguel A. Univ Iowa Dept Otolaryngol Head & Neck Surg Iowa City IA 52242 USA Ramon & Cajal Inst Hlth Res IRYCIS Unidad Genet Mol Madrid Spain Biomed Network Res Ctr Rare Dis CIBERER Madrid Spain Hosp Univ Marques Valdecilla Serv Otorrinolaringol Santander Spain Childrens Med Ctr Dayton Dept Genet Dayton OH USA Univ Iowa Dept Biomed Engn Iowa City IA 52242 USA Univ Iowa Ctr Bioinformat & Computat Biol Iowa City IA 52242 USA Univ Antwerp Dept Med Genet B-2020 Antwerp Belgium Univ Iowa Dept Elect & Comp Engn Iowa City IA 52242 USA Southampton Univ Hosp NHS Trust Wessex Clin Genet Serv Southampton SO16 5YA Hants England Univ Iowa Dept Ophthalmol Iowa City IA 52242 USA Univ Iowa Dept Visual Sci Iowa City IA 52242 USA Radboud Univ Nijmegen Med Ctr Dept Otorhinolaryngol NL-6525 ED Nijmegen Netherlands Radboud Univ Nijmegen Med Ctr Dept Human Genet NL-6525 ED Nijmegen Netherlands Radboud Univ Nijmegen Med Ctr Nijmegen Ctr Mol Life Sci NL-6525 ED Nijmegen Netherlands Radboud Univ Nijmegen Med Ctr Donders Inst Brain Cognit & Behav NL-6525 ED Nijmegen Netherlands Univ Iowa Dept Otolaryngol Interdept PhD Program Genet Iowa City IA 52242 USA

The prevalence of DFNA8/DFNA12 (DFNA8/12), a type of autosomal dominant nonsyndromic hearing loss (ADNSHL), is unknown as comprehensive population-based genetic screening has not been conducted. We therefore completed unbiased screening for TECTA mutations in a Spanish cohort of 372 probands from ADNSHL families. Three additional families (Spanish, Belgian, and English) known to be linked to DFNA8/12 were also included in the screening. In an additional cohort of 835 American ADNSHL families, we preselected 73 probands for TECTA screening based on audiometric data. In aggregate, we identified 23 TECTA mutations in this process. Remarkably, 20 of these mutations are novel, more than doubling the number of reported TECTA ADNSHL mutations from 13 to 33. Mutations lie in all domains of the a-tectorin protein, including those for the first time identified in the entactin domain, as well as the vWFD1, vWFD2, and vWFD3 repeats, and the D1-D2 and TIL2 connectors. Although the majority are private mutations, four of ***1036Tyr, ***1837Gly, ***1866Met, and ***1890Cys-were observed in more than one unrelated family. For two of these mutations founder effects were also confirmed. Our data validate previously observed genotype-phenotype correlations in DFNA8/12 and introduce new correlations. Specifically, mutations in the N-terminal region of a-tectorin (entactin domain, vWFD1, and vWFD2) lead to mid-frequency NSHL, a phenotype previously associated only with mutations in the ZP domain. Collectively, our results indicate that DFNA8/12 hearing loss is a frequent type of ADNSHL. Hum Mutat 32:825-834, 2011. (C) 2011 Wiley-Liss, Inc.

关键词： DFNA8 DFNA12 TECTA mid-frequency hearing loss high-frequency hearing loss

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Genetic variants in the RELN gene are associated with otosclerosis in multiple European populations

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HUMAN GENETICS 2010年第2期127卷 155-162页

作者： schrauwen, isabelle Ealy, Megan Fransen, Erik Vanderstraeten, Kathleen Thys, Melissa Meyer, Nicole C. Cosgarea, Marcel Huber, Alex Mazzoli, Manuela Pfister, Markus Smith, Richard J. H. Van Camp, Guy Univ Iowa Mol Otolaryngol Res Labs Dept Otolaryngol Iowa City IA 52242 USA Univ Antwerp Dept Med Genet B-2610 Antwerp Belgium Iuliu Hatieganu Univ Med & Pharm ENT Dept Cluj Napoca Romania Univ Zurich Hosp Dept Otorhinolaryngol Head & Neck Surg CH-8091 Zurich Switzerland Univ Padua Dept Otosurg I-35128 Padua Italy Univ Tubingen Dept Otorhinolaryngol Tubingen Germany

Otosclerosis is a common form of hearing loss characterized by abnormal bone remodeling in the otic capsule. It is considered a complex disease caused by both genetic and environmental factors. In a previous study, we identified a region on chr7q22.1 located in the RELN gene that is associated with otosclerosis in Belgian-Dutch and French populations. Evidence for allelic heterogeneity was found in this chromosomal region in the form of two independent signals. To confirm this finding, we have completed a replication study that includes four additional populations from Europe (1,141 total samples). Several SNPs in this region replicated in these populations separately. While the power to detect significant association in each population is small, when all four populations are combined, six of seven SNPs replicate and show an effect in the same direction as in the previous populations. We also confirmed the presence of allelic heterogeneity in this region. These data further implicate RELN in the pathogenesis of otosclerosis. Functional research is warranted to determine the pathways through which RELN acts in the pathogenesis of otosclerosis.

关键词： Cell Adhesion Molecules Neuronal/*genetics Extracellular Matrix Proteins/*genetics Female Gene Frequency Genetic Heterogeneity Genotype Germany Hearing Tests Humans Italy Linkage Disequilibrium Logistic Models Male Meta-Analysis as Topic Nerve Tissue Proteins/*genetics Otosclerosis/diagnosis/*genetics Polymorphism Single Nucleotide Romania Serine Endopeptidases/*genetics Switzerland

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