Abstract:
:Common variants in the transcription factor 7-like 2 (TCF7L2) gene have been identified as the strongest genetic risk factors for type 2 diabetes (T2D). However, the mechanisms by which these non-coding variants increase risk for T2D are not well-established. We used 13 expression assays to survey mRNA expression of multiple TCF7L2 splicing forms in up to 380 samples from eight types of human tissue (pancreas, pancreatic islets, colon, liver, monocytes, skeletal muscle, subcutaneous adipose tissue and lymphoblastoid cell lines) and observed a tissue-specific pattern of alternative splicing. We tested whether the expression of TCF7L2 splicing forms was associated with single nucleotide polymorphisms (SNPs), rs7903146 and rs12255372, located within introns 3 and 4 of the gene and most strongly associated with T2D. Expression of two splicing forms was lower in pancreatic islets with increasing counts of T2D-associated alleles of the SNPs: a ubiquitous splicing form (P = 0.018 for rs7903146 and P = 0.020 for rs12255372) and a splicing form found in pancreatic islets, pancreas and colon but not in other tissues tested here (P = 0.009 for rs12255372 and P = 0.053 for rs7903146). Expression of this form in glucose-stimulated pancreatic islets correlated with expression of proinsulin (r(2) = 0.84-0.90, P < 0.00063). In summary, we identified a tissue-specific pattern of alternative splicing of TCF7L2. After adjustment for multiple tests, no association between expression of TCF7L2 in eight types of human tissue samples and T2D-associated genetic variants remained significant. Alternative splicing of TCF7L2 in pancreatic islets warrants future studies. GenBank Accession Numbers: FJ010164-FJ010174.
journal_name
Hum Mol Genetjournal_title
Human molecular geneticsauthors
Prokunina-Olsson L,Welch C,Hansson O,Adhikari N,Scott LJ,Usher N,Tong M,Sprau A,Swift A,Bonnycastle LL,Erdos MR,He Z,Saxena R,Harmon B,Kotova O,Hoffman EP,Altshuler D,Groop L,Boehnke M,Collins FS,Hall JLdoi
10.1093/hmg/ddp321subject
Has Abstractpub_date
2009-10-15 00:00:00pages
3795-804issue
20eissn
0964-6906issn
1460-2083pii
ddp321journal_volume
18pub_type
杂志文章abstract::Mitochondrial DNA (mtDNA) depletion syndrome (MDS), an autosomal recessive condition, is characterized by variable organ involvement with decreased mtDNA copy number and activities of respiratory chain enzymes in affected tissues. MtDNA depletion has been associated with mutations in nine autosomal genes, including th...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddn143
更新日期:2008-08-15 00:00:00
abstract::Glycogen storage disease type II (GSDII) or Pompe disease is an autosomal recessive disorder caused by defects in the acid alpha-glucosidase gene, which leads to lysosomal glycogen accumulation and enlargement of the lysosomes mainly in cardiac and muscle tissues, resulting in fatal hypertrophic cardiomyopathy and res...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddn290
更新日期:2008-12-15 00:00:00
abstract::Mutations in the human PAX6 gene produce various phenotypes, including aniridia, Peters' anomaly, autosomal dominant keratitis and familial foveal dysplasia. The various phenotypes may arise from different mutations in the same gene. To test this theory, we performed a functional analysis of two missense mutations in ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/6.3.381
更新日期:1997-03-01 00:00:00
abstract::The tumour suppressor gene PTEN encodes a dual-specificity phosphatase that recognizes protein substrates and phosphatidylinositol-3,4,5-triphosphate. PTEN seems to play multiple roles in tumour suppression and the blockade of phosphoinositide-3-kinase signalling is important for its growth suppressive effects, althou...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/10.6.605
更新日期:2001-03-15 00:00:00
abstract::Hirschsprung disease (HSCR, aganglionic megacolon) is a frequent congenital malformation regarded as a multigenic neurocristopathy. Two susceptibility genes have been recently identified in HSCR, namely the RET proto-oncogene and the endothelin B receptor (EDNRB) gene. Hitherto however, homozygosity for EDNRB mutation...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/5.3.355
更新日期:1996-03-01 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::Niemann-Pick type C disease (NP-C) is a progressive lysosomal lipid storage disease caused by mutations in the NPC1 and NPC2 genes. NPC1 is essential for transporting cholesterol and other lipids out of lysosomes, but little is known about the mechanisms that control its cellular abundance and localization. Here we sh...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddw204
更新日期:2016-08-15 00:00:00
abstract::NADH-ubiquinone oxidoreductase (complex I) deficiency is amongst the most encountered defects of the mitochondrial oxidative phosphorylation (OXPHOS) system and is associated with a wide variety of clinical signs and symptoms. Mutations in complex I nuclear structural genes are the most common cause of isolated comple...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddh071
更新日期:2004-03-15 00:00:00
abstract::Germline mutations in the RB1 gene confer hereditary predisposition to retinoblastoma. The majority of these mutations occur de novo and differ from one patient to another. Cytogenetics and Southern blotting were shown to detect less than 15% of constitutional rearrangements. In this study we used the polymerase chain...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/2.7.975
更新日期:1993-07-01 00:00:00
abstract::Aberrant tau protein accumulation drives neurofibrillary tangle (NFT) formation in several neurodegenerative diseases. Currently, efforts to elucidate pathogenic mechanisms and assess the efficacy of therapeutic targets are limited by constraints of existing models of tauopathy. In order to generate a more versatile m...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddv336
更新日期:2015-11-01 00:00:00
abstract::Large expansions of hexanucleotide GGGGCC (G4C2) repeats (hundreds to thousands) in the first intron of the chromosome 9 open reading frame 72 (C9orf72) locus are the strongest known genetic factor associated with amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Different hypotheses exist about the...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddy083
更新日期:2018-05-15 00:00:00
abstract::Spinocerebellar ataxia 2 (SCA2) is an autosomal dominant neurodegenerative disorder that results from the expansion of a cryptic CAG repeat within the exon 1 of the SCA2 gene. The CAG repeat in normal individuals varies in length from 14 to 31 repeats and is frequently interrupted by one or more CAA triplets, whereas ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/10.21.2437
更新日期:2001-10-01 00:00:00
abstract::Mutations in subunits or regulators of cohesin cause a spectrum of disorders in humans known as the 'cohesinopathies'. Cohesinopathies, including the best known example Cornelia de Lange syndrome (CdLS), are characterized by broad spectrum, multifactorial developmental anomalies. Heart defects occur at high frequency ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddv402
更新日期:2015-12-15 00:00:00
abstract::Manipulation of the mouse genome by site-specific mutagenesis has been extensively used to study gene function and model human disorders. Mouse models of myotubular myopathy (XLMTM), a severe congenital muscular disorder due to loss-of-function mutations in the MTM1 gene, have been generated by homologous recombinatio...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddt038
更新日期:2013-05-01 00:00:00
abstract::Polyglutamine expansions in the huntingtin gene cause Huntington's disease (HD). Huntingtin is ubiquitously expressed, leading to pathological alterations also in peripheral organs. Variations in the length of the polyglutamine tract explain up to 70% of the age-at-onset variance, with the rest of the variance attribu...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddy077
更新日期:2018-05-15 00:00:00
abstract::Selective loss of dopaminergic neurons is the final common pathway in Parkinson's disease. Expression of Parkin associated endothelin-receptor like receptor (Pael-R) in mouse brain was achieved by injecting adenoviral vectors carrying a modified neuron-specific promoter and Cre recombinase into the striatum. Upregulat...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddl439
更新日期:2007-01-01 00:00:00
abstract::A vast portion of intellectual disability and autism spectrum disorders is genetically caused by mutations in chromatin modulators. These proteins play key roles in development and are also highly expressed in the adult brain. Specifically, the pivotal role of chromatin regulation in transcription has placed enhancers...
journal_title:Human molecular genetics
pub_type: 杂志文章,评审
doi:10.1093/hmg/ddz196
更新日期:2019-11-21 00:00:00
abstract::Spinal muscular atrophy (SMA) is a neuromuscular disease caused by mutations in survival motor neuron 1 (SMN1). SMN-restoring therapies have recently emerged; however, preclinical and clinical studies revealed a limited therapeutic time window and systemic aspects of the disease. This raises a fundamental question of ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddaa146
更新日期:2020-09-29 00:00:00
abstract::Chediak-Higashi syndrome is an autosomal recessive, immune deficiency disorder of human (CHS) and mouse (beige, bg) that is characterized by abnormal intracellular protein transport to, and from, the lysosome. Recent reports have described the identification of homologous genes that are mutated in human CHS and bg mic...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/6.7.1091
更新日期:1997-07-01 00:00:00
abstract::Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2) is the most severe form of human lipodystrophy and is caused by loss-of-function mutations in the BSCL2/seipin gene. Exactly how seipin may regulate adipogenesis remains unclear. A recent study in vitro suggested that seipin may function to inhibit the activity...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddz300
更新日期:2020-02-01 00:00:00
abstract::Cigarette smoking is a leading modifiable cause of death worldwide. We hypothesized that cigarette smoking induces extensive transcriptomic changes that lead to target-organ damage and smoking-related diseases. We performed a meta-analysis of transcriptome-wide gene expression using whole blood-derived RNA from 10,233...
journal_title:Human molecular genetics
pub_type: 杂志文章,meta分析
doi:10.1093/hmg/ddw288
更新日期:2016-11-01 00:00:00
abstract::The striated muscle sarcomeres are highly organized structures composed of actin (thin) and myosin (thick) filaments that slide past each other during contraction. The integrity of sarcomeres is controlled by a set of structural proteins, among which are titin, a giant molecule that contains several immunoglobulin (Ig...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/8.7.1329
更新日期:1999-07-01 00:00:00
abstract::Age-related macular degeneration (AMD) is a progressive neurodegenerative disease, which affects quality of life for millions of elderly individuals worldwide. AMD is associated with a diverse spectrum of clinical phenotypes, all of which include the death of photoreceptors in the central part of the human retina (cal...
journal_title:Human molecular genetics
pub_type: 杂志文章,评审
doi:10.1093/hmg/ddm212
更新日期:2007-10-15 00:00:00
abstract::A spectrum of complex oligogenic disorders called the ciliopathies have been connected to dysfunction of cilia. Among the ciliopathies are Nephronophthisis (NPHP), characterized by cystic kidney disease and retinal degeneration, and Meckel-Gruber syndrome (MKS), a gestational lethal condition with skeletal abnormaliti...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddr198
更新日期:2011-08-01 00:00:00
abstract::The first steps of ether lipid biosynthesis are exclusively localized to peroxisomes and hence some peroxisomal disorders are characterized by a severe deficiency of plasmalogens, the main ether lipids in humans. Here we report on gene defects of plasmalogen biosynthesis, chromosomal localization of the corresponding ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/10.2.127
更新日期:2001-01-15 00:00:00
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::Neonatal dried blood spots (NDBS) are a widely banked sample source that enables retrospective investigation into early life molecular events. Here, we performed low-pass whole genome bisulfite sequencing (WGBS) of 86 NDBS DNA to examine early life Down syndrome (DS) DNA methylation profiles. DS represents an example ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddaa218
更新日期:2021-01-06 00:00:00
abstract::Induced pluripotent stem cell (iPSC)-derived cortical neurons potentially present a powerful new model to understand corticogenesis and neurological disease. Previous work has established that differentiation protocols can produce cortical neurons, but little has been done to characterize these at cellular resolution....
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddv637
更新日期:2016-03-01 00:00:00
abstract::Multicentric chromosomes are often found in tumor cells and certain cell lines. How they are generated is not fully understood, though their stability suggests that they are non-functional during chromosome segregation. Growing evidence has implicated microtubule motor proteins in attachment of chromosomes to the mito...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/7.4.671
更新日期:1998-04-01 00:00:00
abstract::Cilia are evolutionarily conserved organelles endowed with essential physiological and developmental functions. In humans, disruption of cilia motility or signaling leads to complex pleiotropic genetic disorders called ciliopathies. Cilia motility requires the assembly of multi-subunit motile components such as dynein...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddt445
更新日期:2014-02-01 00:00:00