Abstract:
:Nuclear Factor-kappaB (NF-kappaB) is a major transcription regulator of immune response, apoptosis and cell-growth control genes, and is upregulated in inflammatory bowel disease (IBD), both ulcerative colitis (UC) and Crohn's disease. The NFKB1 gene encodes the NF-kappaB p105/p50 isoforms. Genome-wide screens in IBD families show evidence for linkage on chromosome 4q where NFKB1 maps. We sequenced the NFKB1 promoter, exon 1 and all coding exons in 10 IBD probands and two controls, and identified six nucleotide variants, including a common insertion/deletion promoter polymorphism (-94ins/delATTG). Using pedigree-based transmission disequilibrium tests, we observed modest evidence for linkage disequilibrium (LD), independent of linkage, between the -94delATTG allele and UC in 131 out of 235 IBD pedigrees with UC offspring (P=0.047-0.052). This allele was also more frequent in the 156 non-Jewish UC probands from the 235 IBD pedigrees than in 149 non-Jewish controls (P=0.015). The -94delATTG association with UC was replicated in a second set of 258 unrelated, non-Jewish UC cases and 653 new, non-Jewish controls (P=0.021). Nuclear proteins from normal human colon tissue and colonic cell lines, but not ileal tissue, showed significant binding to -94insATTG but not to -94delATTG containing oligonucleotides. NFKB1 promoter/exon 1 luciferase reporter plasmid constructs containing the -94delATTG allele and transfected into either HeLa or HT-29 cell lines showed less promoter activity than comparable constructs containing the -94insATTG allele. Therefore, we have identified the first potentially functional polymorphism of NFKB1 and demonstrated its genetic association with a common human disease, ulcerative colitis.
journal_name
Hum Mol Genetjournal_title
Human molecular geneticsauthors
Karban AS,Okazaki T,Panhuysen CI,Gallegos T,Potter JJ,Bailey-Wilson JE,Silverberg MS,Duerr RH,Cho JH,Gregersen PK,Wu Y,Achkar JP,Dassopoulos T,Mezey E,Bayless TM,Nouvet FJ,Brant SRdoi
10.1093/hmg/ddh008subject
Has Abstractpub_date
2004-01-01 00:00:00pages
35-45issue
1eissn
0964-6906issn
1460-2083pii
ddh008journal_volume
13pub_type
杂志文章abstract::Polyglutamine expansion in certain proteins causes neurodegeneration in inherited disorders such as Huntington disease and X-linked spinobulbar muscular atrophy. Polyglutamine tracts promote protein aggregation in vitro and in vivo with a strict length-dependence that strongly implicates alternative protein folding an...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddl135
更新日期:2006-07-01 00:00:00
abstract::Atopic (allergic) asthma is the most common disease of childhood and is strongly genetic in origin. Many genome-wide screens for asthma and its associated traits have now been carried out, and genetic linkage has been consistently identified in several regions. It is probable that these loci contain major genes influe...
journal_title:Human molecular genetics
pub_type: 杂志文章,评审
doi:10.1093/hmg/9.16.2359
更新日期:2000-10-01 00:00:00
abstract::Smooth muscle cell (SMC) proliferation is a hallmark of vascular injury and disease. Global hypomethylation occurs during SMC proliferation in culture and in vivo during neointimal formation. Regardless of the programmed or stochastic nature of hypomethylation, identifying these changes is important in understanding v...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddt365
更新日期:2013-12-20 00:00:00
abstract::We have established a Drosophila model of Gerstmann-Sträussler-Scheinker (GSS) syndrome by expressing mouse prion protein (PrP) having leucine substitution at residue 101 (MoPrP(P101L)). Flies expressing MoPrP(P101L), but not wild-type MoPrP (MoPrP(3F4)), showed severe defects in climbing ability and early death. Expr...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddq379
更新日期:2010-11-15 00:00:00
abstract::ATRX is a chromatin remodeling protein involved in deposition of the histone variant H3.3 at telomeres and pericentromeric heterochromatin. It also influences the expression level of specific genes; however, deposition of H3.3 at transcribed genes is currently thought to occur independently of ATRX. We focused on a se...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddu596
更新日期:2015-04-01 00:00:00
abstract::It is now well established that the genomic landscape of DNA methylation (DNAm) gets altered as a function of age, a process we here call 'epigenetic drift'. The biological, functional, clinical and evolutionary significance of this epigenetic drift, however, remains unclear. We here provide a brief review of epigenet...
journal_title:Human molecular genetics
pub_type: 杂志文章,评审
doi:10.1093/hmg/ddt375
更新日期:2013-10-15 00:00:00
abstract::The short-rib polydactyly syndromes (SRPS) encompass a radiographically and genetically heterogeneous group of skeletal ciliopathies that are characterized by a long narrow chest, short extremities, and variable occurrence of polydactyly. Radiographic abnormalities include undermineralization of the calvarium, shorten...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddw241
更新日期:2016-09-15 00:00:00
abstract::Mutations in fibroblast growth factor receptors (FGFRs) cause human birth defect syndromes and are associated with a variety of cancers. Although forced expression of mutant activated FGFRs has been shown to oncogenically transform some immortal cell types, their activity in primary cells remains unclear. Here, we sho...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddp195
更新日期:2009-07-15 00:00:00
abstract::The rapid increase in the prevalence of type 2 diabetes (T2D) represents a major challenge for health care delivery worldwide. Identification of genes influencing individual susceptibility to disease offers a route to better understanding of the molecular mechanisms underlying pathogenesis, a necessary prerequisite fo...
journal_title:Human molecular genetics
pub_type: 杂志文章,评审
doi:10.1093/hmg/ddh057
更新日期:2004-04-01 00:00:00
abstract::Epilepsy, deafness, onychodystrophy, osteodystrophy and intellectual disability are associated with a spectrum of mutations of human TBC1D24. The mechanisms underlying TBC1D24-associated disorders and the functions of TBC1D24 are not well understood. Using CRISPR-Cas9 genome editing, we engineered a mouse with a prema...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddy445
更新日期:2019-05-01 00:00:00
abstract::Duchenne muscular dystrophy (DMD) is a lethal X-linked recessive disorder with a high spontaneous mutation rate and no effective treatment, hence development of genetic based therapies is an important goal. We report that expression of a recombinant human minidystrophin cDNA, compatible with current viral vectors, can...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/4.8.1245
更新日期:1995-08-01 00:00:00
abstract::Infantile neuronal ceroid lipofuscinosis (INCL), a neurodegenerative storage disorder of childhood, is caused by mutations in the palmitoyl-protein thioesterase-1 (PPT1) gene. PPT1 cleaves thioester linkages in S-acylated (palmitoylated) proteins and its mutation causes abnormal intracellular accumulation of fatty-acy...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddl105
更新日期:2006-06-01 00:00:00
abstract::PLEC, the gene encoding the cytolinker protein plectin, has eight tissue-specific isoforms in humans, arising by alternate splicing of the first exon. To date, all PLEC mutations that cause epidermolysis bullosa simplex (EBS) were found in exons common to all isoforms. Due to the ubiquitous presence of plectin in mamm...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddv066
更新日期:2015-06-01 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::Multiple endocrine neoplasia type 2 (MEN 2) is a dominantly inherited cancer syndrome which affects thyroid C cells, and with variable frequency, the adrenal medulla, parathyroid and enteric autonomic ganglia. The syndrome is due to germline mutation in the receptor tyrosine kinase gene, RET. We have recently shown an...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/3.10.1771
更新日期:1994-10-01 00:00:00
abstract::Rod and cone photoreceptors in mammalian retina are generated from common pool(s) of neuroepithelial progenitors. NRL, CRX and NR2E3 are key transcriptional regulators that control photoreceptor differentiation. Mutations in NR2E3, a rod-specific orphan nuclear receptor, lead to loss of rods, increased density of S-co...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddl185
更新日期:2006-09-01 00:00:00
abstract::Adolescent idiopathic scoliosis (AIS) is a complex inherited spinal deformity whose etiology has been elusive. While common genetic variants are associated with AIS, they explain only a small portion of disease risk. To explore the role of rare variants in AIS susceptibility, exome sequence data of 391 severe AIS case...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddv463
更新日期:2016-01-01 00:00:00
abstract::The CFTR gene, in which more than 300 mutations have been described, displays a spectrum of mutations which varies according to ethnic and geographic origin of patients. In this paper we report an exhaustive study of the 27 exons and exon/intron boundaries of a sample of 35 CF patients from Bulgaria which is situated ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/3.1.57
更新日期:1994-01-01 00:00:00
abstract::Deficiencies in the complex I (CI; NADH-ubiquinone oxidoreductase) of the respiratory chain are frequent causes of mitochondrial diseases and have been associated with other neurodegenerative disorders, such as Parkinson's disease. The NADH-ubiquinone oxidoreductase 1 alpha subcomplex subunit 5 (NDUFA5) is a nuclear-e...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddt526
更新日期:2014-03-15 00:00:00
abstract::Menkes disease is an X-linked recessive copper deficiency disorder caused by mutations in the ATP7A (MNK) gene. The MNK gene encodes a copper-transporting P-type ATPase, MNK, which is localized predominantly in the trans-Golgi network (TGN). The MNK protein relocates to the plasma membrane in cells exposed to elevated...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/9.19.2845
更新日期:2000-11-22 00:00:00
abstract::The group of dominant non-dystrophic myotonias, comprising disorders characterized by clinically similar forms of myogenic muscle stiffness, is genetically inhomogeneous. Dominant myotonia congenita (Thomsen's disease) is linked to CLCN1, the gene encoding the major muscle chloride channel, localized on chromosome 7q3...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/4.8.1397
更新日期:1995-08-01 00:00:00
abstract::Genomic data offer a goldmine of information for understanding the contribution of genetic variation makes to health and disease. The potential of genomic medicine, to predict, diagnose, manage and treat genetic disease, is underpinned by accurate variant interpretation. This in itself hinges on the ability to access ...
journal_title:Human molecular genetics
pub_type: 杂志文章,评审
doi:10.1093/hmg/ddy084
更新日期:2018-05-01 00:00:00
abstract::Mitochondrial dysfunction and oxidative stress are central to the molecular pathology of many human diseases. Riboflavin responsive multiple acyl-CoA dehydrogenation deficiency (RR-MADD) is in most cases caused by variations in the gene coding for electron transfer flavoprotein-ubiquinone oxidoreductase (ETF-QO). Curr...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddu146
更新日期:2014-08-15 00:00:00
abstract::Linkage analysis of type 1 diabetes sib pair families (n = 334) has suggested two separate regions of human chromosome 6q are linked to disease (designated IDDM5 and IDDM8). To test if these are false positive results, all available sib pair families (n = 429) were typed using a 92% informative map of chromosome 6q an...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/5.7.1071
更新日期:1996-07-01 00:00:00
abstract::Cockayne syndrome (CS) is a human premature aging disorder associated with neurological and developmental abnormalities, caused by mutations mainly in the CS group B gene (ERCC6). At the molecular level, CS is characterized by a deficiency in the transcription-couple DNA repair pathway. To understand the role of this ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/dds211
更新日期:2012-09-01 00:00:00
abstract::Uniparental disomy (UPD) is defined as the inheritance of both homologs of a given genomic region from only one parent. The majority of UPD includes an entire chromosome. However, the extent of UPD is sometimes limited to a subchromosomal region (segmental UPD). Mosaic paternal UPD (pUPD) of chromosome 11 is found in ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddw023
更新日期:2016-04-01 00:00:00
abstract::Following a screen for neuromuscular mouse mutants, we identified ostes, a novel N-ethyl N-nitrosourea-induced mouse mutant with muscle atrophy. Genetic and biochemical evidence shows that upregulation of the novel, uncharacterized transient receptor potential polycystic (TRPP) channel PKD1L2 (polycystic kidney diseas...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddp304
更新日期:2009-10-01 00:00:00
abstract::Mutations in Alsin are associated with chronic juvenile amyotrophic lateral sclerosis (ALS2), juvenile primary lateral sclerosis and infantile-onset ascending spastic paralysis. The primary pathology and pathogenic mechanism of the disease remain largely unknown. Here we show that alsin-deficient mice have motor impai...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddm251
更新日期:2007-12-01 00:00:00
abstract::X-linked spinal and bulbar muscular atrophy (SBMA; Kennedy's disease) is a polyglutamine (polyQ) disease in which the affected males suffer progressive motor neuron degeneration accompanied by signs of androgen insensitivity, such as gynecomastia and reduced fertility. SBMA is caused by CAG repeat expansions in the an...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddl148
更新日期:2006-07-15 00:00:00
abstract::Peripheral sensory perception is established through an elaborate network of specialized neurons that mediate the translation of extraorganismal stimuli through the use of a broad array of receptors and downstream effector molecules. Studies of human genetic disorders, as well as mouse and other animal models, have id...
journal_title:Human molecular genetics
pub_type: 杂志文章,评审
doi:10.1093/hmg/ddp412
更新日期:2009-10-15 00:00:00