Abstract:
:We report identification of a novel genetic locus (GLC1P) for normal tension glaucoma (NTG) on chromosome 12q14 using linkage studies of an African-American pedigree (maximum non-parametric linkage score = 19.7, max LOD score = 2.7). Subsequent comparative genomic hybridization and quantitative polymerase chain reaction (PCR) experiments identified a 780 kbp duplication within the GLC1P locus that is co-inherited with NTG in the pedigree. Real-time PCR studies showed that the genes within this duplication [TBK1 (TANK-binding kinase 1), XPOT, RASSF3 and GNS] are all expressed in the human retina. Cohorts of 478 glaucoma patients (including 152 NTG patients), 100 normal control subjects and 400 age-related macular degeneration patients were subsequently tested for copy number variation in GLC1P. Overlapping duplications were detected in 2 (1.3%) of the 152 NTG subjects, one of which had a strong family history of glaucoma. These duplications defined a 300 kbp critical region of GLC1P that spans two genes (TBK1 and XPOT). Microarray expression experiments and northern blot analysis using RNA obtained from human skin fibroblast cells showed that duplication of chromosome 12q14 results in increased TBK1 and GNS transcription. Finally, immunohistochemistry studies showed that TBK1 is expressed in the ganglion cells, nerve fiber layer and microvasculature of the human retina. Together, these data link the duplication of genes on chromosome 12q14 with familial NTG and suggest that an extra copy of the encompassed TBK1 gene is likely responsible for these cases of glaucoma. However, animal studies will be necessary to rule out a role for the other duplicated or neighboring genes.
journal_name
Hum Mol Genetjournal_title
Human molecular geneticsauthors
Fingert JH,Robin AL,Stone JL,Roos BR,Davis LK,Scheetz TE,Bennett SR,Wassink TH,Kwon YH,Alward WL,Mullins RF,Sheffield VC,Stone EMdoi
10.1093/hmg/ddr123subject
Has Abstractpub_date
2011-06-15 00:00:00pages
2482-94issue
12eissn
0964-6906issn
1460-2083pii
ddr123journal_volume
20pub_type
杂志文章abstract::Amyotrophic lateral sclerosis (ALS) is a progressive motor neurodegeneration resulting in paralysis and death from respiratory failure within 3-5 years. About 20% of familial cases are associated with mutations in the gene for copper/zinc superoxide dismutase ( SOD1 ), which catalyses the dismutation of the superoxide...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/7.13.2045
更新日期:1998-12-01 00:00:00
abstract::Myotonic dystrophy type 1 (DM1), the most common form of adult-onset muscular dystrophy, is caused by an expanded (CTG)n repeat in the 3' untranslated region of the DM protein kinase (DMPK) gene. The toxic RNA transcripts produced from the mutant allele alter the function of RNA-binding proteins leading to the functio...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddt419
更新日期:2014-01-15 00:00:00
abstract::The survival of motor neuron (SMN) protein is mutated in patients with spinal muscular atrophy (SMA). SMN is part of a multiprotein complex required for biogenesis of the Sm class of small nuclear ribonucleoproteins (snRNPs). Following assembly of the Sm core domain, snRNPs are transported to the nucleus via importin ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/11.15.1785
更新日期:2002-07-15 00:00:00
abstract::Fourteen neurological diseases have been associated with the expansion of trinucleotide repeat regions. These diseases have been categorized into those that give rise to the translation of toxic polyglutamine proteins and those that are untranslated. Thus far, compelling evidence has not surfaced for the inclusion of ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/10.15.1531
更新日期:2001-07-15 00:00:00
abstract::We describe a method for rapid identification of chromosomes at metaphase, and quantification of chromosomes in interphase, by annealing oligonucleotide primers, derived from chromosome-specific subsets of repeated DNA families, to the DNA of cytological preparations, and enzymatic extension with the incorporation of ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/3.6.931
更新日期:1994-06-01 00:00:00
abstract::We introduced a targeted single base deletion at codon 307 of the rds-peripherin gene in mice, similar mutations being known to cause autosomal dominant retinitis pigmentosa (RP) in man. Histopathological and electroretinographic analysis indicate that the retinopathy in mice homozygous for the codon 307 mutation appe...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/11.9.1005
更新日期:2002-05-01 00:00:00
abstract::Mutations in SOX18, VEGFC and Vascular Endothelial Growth Factor 3 underlie the hereditary lymphatic disorders hypotrichosis-lymphedema-telangiectasia (HLT), Milroy-like lymphedema and Milroy disease, respectively. Genes responsible for hereditary lymphedema are key regulators of lymphatic vascular development in the ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddt518
更新日期:2014-03-01 00:00:00
abstract::Age-related macular degeneration (AMD) is a progressive disease of the central retina and the leading cause of irreversible vision loss in the western world. The involvement of abnormal complement activation in AMD has been suggested by association of variants in genes encoding complement proteins with disease develop...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddy178
更新日期:2018-08-01 00:00:00
abstract::Alzheimer's disease (AD) and related tauopathies comprise a large group of neurodegenerative diseases associated with the pathological aggregation of tau protein. While much effort has focused on understanding the function of tau, little is known about the endogenous mechanisms regulating tau metabolism in vivo and ho...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddv377
更新日期:2015-12-01 00:00:00
abstract::To determine factors governing triplet repeat expansion at FMR1, we need to understand the basis of normal variation. We have sequenced the FMR1 repeat from 102 normal X chromosomes and show that most are interrupted with a regularly spaced AGG trinucleotide giving an ordered structure to the array. Five types of arra...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/3.9.1553
更新日期:1994-09-01 00:00:00
abstract::Mutations in the presenilin 1 ( PSEN1 ) gene have been implicated in 18-50% of autosomal dominant cases with early-onset Alzheimer's disease (EOAD). Also, PSEN1 has been suggested as a potential risk gene in late-onset AD cases. We recently showed genetic association in a population-based study of EOAD, pointing to th...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/9.3.325
更新日期:2000-02-12 00:00:00
abstract::Migraine is a prevalent, debilitating and costly disorder with an ongoing unmet medical need. Human genetic studies have provided considerable insights into the molecular underpinnings of this complex brain disorder. Classical linkage studies have revealed the causes of familial hemiplegic migraine, while more recentl...
journal_title:Human molecular genetics
pub_type: 杂志文章,评审
doi:10.1093/hmg/ddt364
更新日期:2013-10-15 00:00:00
abstract::Research of cilia has gained significant momentum in the last 15 years, as an increasing number of human genetic diseases were found to be caused by disruption of a protein that localizes to cilia. These ciliopathies are as diverse as the functions of the associated proteins, covering a spectrum of overlapping phenoty...
journal_title:Human molecular genetics
pub_type: 杂志文章,评审
doi:10.1093/hmg/ddr354
更新日期:2011-10-15 00:00:00
abstract::The FKHR gene, which contains a forkhead DNA-binding motif, is fused to either PAX3 or PAX7 by the t(2;13) or t(1;13) translocation in alveolar rhabdomyosarcoma,respectively. These tumors express chimeric transcripts encoding the N-terminal portion of either PAX protein fused to the C-terminal portion of FKHR. To unde...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/4.12.2355
更新日期:1995-12-01 00:00:00
abstract::HTRA2-BETA1 is an SR-like protein that regulates alternative splice site selection in a concentration-dependent manner. Its proper concentration is important as several pathological states are associated with its change. We investigated the mechanism that controls the cellular HTRA2-BETA1 concentration and found it ut...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddh051
更新日期:2004-03-01 00:00:00
abstract::The fields of both developmental and stem cell biology explore how functionally distinct cell types arise from a self-renewing founder population. Multipotent, proliferative human neural crest cells (hNCC) develop toward the end of the first month of pregnancy. It is assumed that most differentiate after migrating thr...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddn235
更新日期:2008-11-01 00:00:00
abstract::Linkage, association and postmortem studies have implicated regulator of G-protein signaling 4 (RGS4), which negatively modulates signal transduction at G-protein-coupled receptors, as a candidate schizophrenia susceptibility gene. We compared RGS4 mRNA expression in the dorsolateral prefrontal cortex (DLPFC), between...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddl222
更新日期:2006-09-15 00:00:00
abstract::The positions of DNA replication initiation regions (IRs) at three human trinucleotide repeat (TNR) disease loci were examined in order to characterize the role played by IRs in explaining the known locus-specific variation in TNR instability levels. Using three different normal cell lines, candidate IRs were identifi...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddg111
更新日期:2003-05-01 00:00:00
abstract:BACKGROUND:Single variant approaches have been successful in identifying DNA methylation quantitative trait loci (mQTL), although as with complex traits they lack the statistical power to identify the effects from rare genetic variants. We have undertaken extensive analyses to identify regions of low frequency and rare...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddw283
更新日期:2016-10-01 00:00:00
abstract::To elucidate the molecular mechanisms of impaired elastic fiber formation in recessive cutis laxa, we have investigated two disease-causing missense substitutions in fibulin-5, C217R and S227P. Pulse-chase immunoprecipitation experiments indicated that S227P mutant fibulin-5 was synthesized and secreted by skin fibrob...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddl414
更新日期:2006-12-01 00:00:00
abstract::Newborn screening (NBS) for medium-chain acyl-CoA dehydrogenase deficiency (MCADD) revealed a higher birth prevalence and genotypic variability than previously estimated, including numerous novel missense mutations in the ACADM gene. On average, these mutations are associated with milder biochemical phenotypes raising...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddp079
更新日期:2009-05-01 00:00:00
abstract::Protein-protein interactions are fundamental to all biological processes, and a comprehensive determination of all protein-protein interactions that can take place in an organism provides a framework for understanding biology as an integrated system. The availability of genome-scale sets of cloned open reading frames ...
journal_title:Human molecular genetics
pub_type: 杂志文章,评审
doi:10.1093/hmg/ddi335
更新日期:2005-10-15 00:00:00
abstract::Proximal spinal muscular atrophy (SMA) is caused by mutations in the survival motor neuron gene (SMN1). In humans, two nearly identical copies of SMN exist and differ only by a single non-polymorphic C-->T nucleotide transition in exon 7. SMN1 contains a 'C' nucleotide at the +6 position of exon 7 and produces primari...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/10.23.2727
更新日期:2001-11-01 00:00:00
abstract::Peroxisomes are vital eukaryotic organelles that participate in lipid metabolism, in particular the metabolism of very-long-chain fatty acids (VLCFA). The biogenesis of peroxisomes is regulated by a set of peroxin proteins (PEX). In humans, mutations affecting peroxin protein production or function result in devastati...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddp518
更新日期:2010-02-01 00:00:00
abstract::The human gene HIC1 (hypermethylated in cancer) maps to chromosome 17p13.3 and is deleted in the contiguous gene disorder Miller-Dieker syndrome (MDS) [Makos-Wales et al. (1995) Nature Med., 1, 570-577; Chong et al. (1996) Genome Res., 6, 735-741]. We isolated the murine homologue Hic1, encoding a zinc-finger protein ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/8.4.697
更新日期:1999-04-01 00:00:00
abstract::The purpose of this study was to determine whether thrombospondin (TSP)-1 promotes macrophage activity and disease progression in dysferlinopathy. First, we found that levels of TSP-1 are elevated in blood of non-ambulant dysferlinopathy patients compared with ambulant patients and healthy controls, supporting the ide...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddx378
更新日期:2017-12-15 00:00:00
abstract::Alternative splicing emerges as one of the most important mechanisms to generate transcript diversity. It is regulated by the formation of protein complexes on pre-mRNA. We demonstrate that protein phosphatase 1 (PP1) binds to the splicing factor transformer2-beta1 (tra2-beta1) via a phylogenetically conserved RVDF se...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddm284
更新日期:2008-01-01 00:00:00
abstract::What would define real progress in the field of deafness research in fundamental and medical terms? In fundamental terms, progress would be measured by an improvement in our knowledge of the development and physiology of the ear. In medical terms, progress would lead to the division of the broad category of hearing de...
journal_title:Human molecular genetics
pub_type: 杂志文章,评审
doi:10.1093/hmg/7.10.1589
更新日期:1998-01-01 00:00:00
abstract::Human embryo development occurs through a process that encompasses reprogramming, sequential cleavage divisions and mitotic chromosome segregation and embryonic genome activation. Chromosomal abnormalities may arise during germ cell and/or pre-implantation embryo development, and are a major cause of spontaneous misca...
journal_title:Human molecular genetics
pub_type: 杂志文章,评审
doi:10.1093/hmg/ddn170
更新日期:2008-04-15 00:00:00
abstract::The lifetime accumulation of low-abundance, somatic mtDNA re-arrangements (sublimons) has been proposed as a potential contributor to aging, and also to diseases such as cardiomyopathy or coronary heart disease. Tissue-specific sublimons, varying in abundance by three orders of magnitude between individuals, have rece...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/11.3.317
更新日期:2002-02-01 00:00:00