Splicing modulation of integrin beta4 pre-mRNA carrying a branch point mutation underlies epidermolysis bullosa with pyloric atresia undergoing spontaneous amelioration with ageing.

Abstract:

:A general improvement with ageing has been reported in a few cases of epidermolysis bullosa with pyloric atresia (PA-JEB), an autosomal recessive skin disease characterized by extensive disadhesion of epithelia. In a patient who improved from severe to mild PA-JEB, a search for mutations in the integrin beta4 gene (IGTB4) detected heterozygosity for a novel base substitution 3986-19T-->A in the putative branchpoint sequence of intron 31, and a point mutation 3802+1G-->A in the donor splice site of intron 30 previously associated with severe PA-JEB. Analysis of mRNA showed that the intronic mutation prevents legitimate splicing of the beta4 pre-mRNA. Functional splicing can be restored in vitro by seeding the proband's keratinocytes on feeders of irradiated fibroblasts. Study of mRNA in wild-type keratinocytes transfected with IGTB4 minigenes containing intron 31 with or without mutation 3986-19T-->A, confirmed the causative role of the intronic mutation in PA-JEB, and highlighted the influence of feeders on the maturation process of the mutated beta4 pre-mRNA. Our results show that in a context of overall reduction of the beta4 mRNA levels, activation of the legitimate splice site in the aberrant beta4 pre-mRNA underlies the transient severity of the condition. The results also point to the relevance which the interaction between epithelial and stromal cells may have in modulating expression of integrin receptors.

journal_name

Hum Mol Genet

journal_title

Human molecular genetics

authors

Chavanas S,Gache Y,Vailly J,Kanitakis J,Pulkkinen L,Uitto J,Ortonne J,Meneguzzi G

doi

10.1093/hmg/8.11.2097

subject

Has Abstract

pub_date

1999-10-01 00:00:00

pages

2097-105

issue

11

eissn

0964-6906

issn

1460-2083

pii

ddc234

journal_volume

8

pub_type

杂志文章
  • BLM helicase facilitates RNA polymerase I-mediated ribosomal RNA transcription.

    abstract::Bloom's syndrome (BS) is an autosomal recessive disorder that is invariably characterized by severe growth retardation and cancer predisposition. The Bloom's syndrome helicase (BLM), mutations of which lead to BS, localizes to promyelocytic leukemia protein bodies and to the nucleolus of the cell, the site of RNA poly...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/ddr545

    authors: Grierson PM,Lillard K,Behbehani GK,Combs KA,Bhattacharyya S,Acharya S,Groden J

    更新日期:2012-03-01 00:00:00

  • Cloning and characterization of the human choroideremia gene.

    abstract::Positional cloning has previously resulted in the identification of a gene which is disrupted by deletions in patients with the classic choroideremia (CHM) phenotype. More subtle mutations had been identified in 4 exons of the 3' portion but not elsewhere in the CHM gene. We have now isolated and characterized the com...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/3.7.1041

    authors: van Bokhoven H,van den Hurk JA,Bogerd L,Philippe C,Gilgenkrantz S,de Jong P,Ropers HH,Cremers FP

    更新日期:1994-07-01 00:00:00

  • Deficiency of the E3 ubiquitin ligase TRIM2 in early-onset axonal neuropathy.

    abstract::Inherited peripheral neuropathies are a heterogeneous group of disorders that can affect patients of all ages. Children with inherited neuropathy often develop severe disability, but the genetic causes of recessive early-onset axonal neuropathies are not fully known. We have taken a whole-exome sequencing approach to ...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/ddt149

    authors: Ylikallio E,Pöyhönen R,Zimon M,De Vriendt E,Hilander T,Paetau A,Jordanova A,Lönnqvist T,Tyynismaa H

    更新日期:2013-08-01 00:00:00

  • Functional variants in TBX2 are associated with a syndromic cardiovascular and skeletal developmental disorder.

    abstract::The 17 genes of the T-box family are transcriptional regulators that are involved in all stages of embryonic development, including craniofacial, brain, heart, skeleton and immune system. Malformation syndromes have been linked to many of the T-box genes. For example, haploinsufficiency of TBX1 is responsible for many...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/ddy146

    authors: Liu N,Schoch K,Luo X,Pena LDM,Bhavana VH,Kukolich MK,Stringer S,Powis Z,Radtke K,Mroske C,Deak KL,McDonald MT,McConkie-Rosell A,Markert ML,Kranz PG,Stong N,Need AC,Bick D,Amaral MD,Worthey EA,Levy S,Undiagnosed

    更新日期:2018-07-15 00:00:00

  • Autozygosity mapping and time-to-spontaneous delivery in Norwegian parent-offspring trios.

    abstract::Parental genetic relatedness may lead to adverse health and fitness outcomes in the offspring. However, the degree to which it affects human delivery timing is unknown. We use genotype data from ≃25 000 parent-offspring trios from the Norwegian Mother, Father and Child Cohort Study to optimize runs of homozygosity (RO...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/ddaa255

    authors: Sole-Navais P,Bacelis J,Helgeland Ø,Modzelewska D,Vaudel M,Flatley C,Andreassen O,Njølstad PR,Muglia LJ,Johansson S,Zhang G,Jacobsson B

    更新日期:2020-12-08 00:00:00

  • SUCLG2 identified as both a determinator of CSF Aβ1-42 levels and an attenuator of cognitive decline in Alzheimer's disease.

    abstract::Cerebrospinal fluid amyloid-beta 1-42 (Aβ1-42) and phosphorylated Tau at position 181 (pTau181) are biomarkers of Alzheimer's disease (AD). We performed an analysis and meta-analysis of genome-wide association study data on Aβ1-42 and pTau181 in AD dementia patients followed by independent replication. An association ...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/ddu372

    authors: Ramirez A,van der Flier WM,Herold C,Ramonet D,Heilmann S,Lewczuk P,Popp J,Lacour A,Drichel D,Louwersheimer E,Kummer MP,Cruchaga C,Hoffmann P,Teunissen C,Holstege H,Kornhuber J,Peters O,Naj AC,Chouraki V,Bellenguez C

    更新日期:2014-12-15 00:00:00

  • Homozygous mutation of PLCZ1 leads to defective human oocyte activation and infertility that is not rescued by the WW-binding protein PAWP.

    abstract::In mammals, sperm-oocyte fusion initiates Ca(2+) oscillations leading to a series of events called oocyte activation, which is the first stage of embryo development. Ca(2+) signaling is elicited by the delivery of an oocyte-activating factor by the sperm. A sperm-specific phospholipase C (PLCZ1) has emerged as the lik...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/ddv617

    authors: Escoffier J,Lee HC,Yassine S,Zouari R,Martinez G,Karaouzène T,Coutton C,Kherraf ZE,Halouani L,Triki C,Nef S,Thierry-Mieg N,Savinov SN,Fissore R,Ray PF,Arnoult C

    更新日期:2016-03-01 00:00:00

  • Parkinson disease protein DJ-1 converts from a zymogen to a protease by carboxyl-terminal cleavage.

    abstract::Mutations in DJ-1 cause recessively transmitted early-onset Parkinson disease (PD), and oxidative damage to DJ-1 has been associated with the pathogenesis of late-onset sporadic PD. The precise biochemical function of DJ-1 remains elusive. Here, we report that DJ-1 is synthesized as a latent protease zymogen with low-...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/ddq113

    authors: Chen J,Li L,Chin LS

    更新日期:2010-06-15 00:00:00

  • Overexpression of a calpastatin transgene in mdx muscle reduces dystrophic pathology.

    abstract::Reduced sarcolemmal integrity in dystrophin-deficient muscles of mdx mice and Duchenne muscular dystrophy (DMD) patients has been reported to result in altered calcium homeostasis. Previous studies have shown a correlative relationship between calcium-dependent protease (calpain) activity in dystrophic muscle and musc...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/11.21.2645

    authors: Spencer MJ,Mellgren RL

    更新日期:2002-10-01 00:00:00

  • Duplication of Glu37 in the switch I region of HRAS impairs effector/GAP binding and underlies Costello syndrome by promoting enhanced growth factor-dependent MAPK and AKT activation.

    abstract::Costello syndrome (CS) is a developmental disorder characterized by postnatal reduced growth, facial dysmorphism, cardiac defects, mental retardation and skin and musculo-skeletal defects. CS is caused by HRAS germline mutations. In the majority of cases, mutations affect Gly(12) and Gly(13) and are associated with a ...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/ddp548

    authors: Gremer L,De Luca A,Merbitz-Zahradnik T,Dallapiccola B,Morlot S,Tartaglia M,Kutsche K,Ahmadian MR,Rosenberger G

    更新日期:2010-03-01 00:00:00

  • mTOR pathway is activated by PKA in adrenocortical cells and participates in vivo to apoptosis resistance in primary pigmented nodular adrenocortical disease (PPNAD).

    abstract::Primary pigmented nodular adrenocortical disease (PPNAD) is associated with inactivating mutations of the PRKAR1A tumor suppressor gene that encodes the regulatory subunit R1α of the cAMP-dependent protein kinase (PKA). In human and mouse adrenocortical cells, these mutations lead to increased PKA activity, which resu...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/ddu265

    authors: de Joussineau C,Sahut-Barnola I,Tissier F,Dumontet T,Drelon C,Batisse-Lignier M,Tauveron I,Pointud JC,Lefrançois-Martinez AM,Stratakis CA,Bertherat J,Val P,Martinez A

    更新日期:2014-10-15 00:00:00

  • Genome-wide association study identifies a novel susceptibility gene for serum TSH levels in Chinese populations.

    abstract::Thyroid-stimulating hormone (TSH) is a sensitive indicator of thyroid function. High and low TSH levels reflect hypothyroidism and hyperthyroidism, respectively. Even within the normal range, small differences in TSH levels, on the order of 0.5-1.0 mU/l, are associated with significant differences in blood pressure, B...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/ddu250

    authors: Zhan M,Chen G,Pan CM,Gu ZH,Zhao SX,Liu W,Wang HN,Ye XP,Xie HJ,Yu SS,Liang J,Gao GQ,Yuan GY,Zhang XM,Zuo CL,Su B,Huang W,Ning G,Chen SJ,Chen JL,Song HD,China Consortium for Genetics of Autoimmune Thyroid Disease.

    更新日期:2014-10-15 00:00:00

  • Detecting tissue-specific alternative splicing and disease-associated aberrant splicing of the PTCH gene with exon junction microarrays.

    abstract::Mutations in the human ortholog of Drosophila patched (PTCH) have been identified in patients with autosomal dominant nevoid basal cell carcinoma syndrome (NBCCS), characterized by minor developmental anomalies and an increased incidence of cancers such as medulloblastoma and basal cell carcinoma. We identified many i...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/ddi369

    authors: Nagao K,Togawa N,Fujii K,Uchikawa H,Kohno Y,Yamada M,Miyashita T

    更新日期:2005-11-15 00:00:00

  • Rare deleterious BUB1B variants induce premature ovarian insufficiency and early menopause.

    abstract::Losing of ovarian functions prior to natural menopause age causes female infertility and early menopause. Premature ovarian insufficiency (POI) is defined as the loss of ovarian activity before 40 years of age. Known genetic causes account for 25-30% of POI cases, demonstrating the high genetic heterogeneity of POI an...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/ddaa153

    authors: Chen Q,Ke H,Luo X,Wang L,Wu Y,Tang S,Li J,Jin L,Zhang F,Qin Y,Chen X

    更新日期:2020-09-29 00:00:00

  • Most genome-wide significant susceptibility loci for schizophrenia and bipolar disorder reported to date cross-traditional diagnostic boundaries.

    abstract::Recent findings from genetic epidemiology and from genome-wide association studies point strongly to a partial overlap in the genes that contribute susceptibility to schizophrenia and bipolar disorder (BD). Previous data have also directly implicated one of the best supported schizophrenia-associated loci, zinc finger...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/ddq471

    authors: Williams HJ,Craddock N,Russo G,Hamshere ML,Moskvina V,Dwyer S,Smith RL,Green E,Grozeva D,Holmans P,Owen MJ,O'Donovan MC

    更新日期:2011-01-15 00:00:00

  • Mutation in exon 1a of PLEC, leading to disruption of plectin isoform 1a, causes autosomal-recessive skin-only epidermolysis bullosa simplex.

    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

    authors: Gostyńska KB,Nijenhuis M,Lemmink H,Pas HH,Pasmooij AM,Lang KK,Castañón MJ,Wiche G,Jonkman MF

    更新日期:2015-06-01 00:00:00

  • Neurological deficits and glycosphingolipid accumulation in saposin B deficient mice.

    abstract::Saposin B derives from the multi-functional precursor, prosaposin, and functions as an activity enhancer for several glycosphingolipid (GSL) hydrolases. Mutations in saposin B present in humans with phenotypes resembling metachromatic leukodystrophy. To gain insight into saposin B's physiological functions, a specific...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/ddn135

    authors: Sun Y,Witte DP,Ran H,Zamzow M,Barnes S,Cheng H,Han X,Williams MT,Skelton MR,Vorhees CV,Grabowski GA

    更新日期:2008-08-01 00:00:00

  • Zebrafish cul4a, but not cul4b, modulates cardiac and forelimb development by upregulating tbx5a expression.

    abstract::CUL4A and CUL4B are closely related cullin family members and can each assemble a Cullin-RING E3 ligase complex (CRL) and participate in a variety of biological processes. While the CRLs formed by the two cullin members may have common targets, the two appeared to have very different consequences when mutated or disru...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/ddu503

    authors: Zhao X,Jiang B,Hu H,Mao F,Mi J,Li Z,Liu Q,Shao C,Gong Y

    更新日期:2015-02-01 00:00:00

  • Knockout of Tmem70 alters biogenesis of ATP synthase and leads to embryonal lethality in mice.

    abstract::TMEM70, a 21-kDa protein localized in the inner mitochondrial membrane, has been shown to facilitate the biogenesis of mammalian F1Fo ATP synthase. Mutations of the TMEM70 gene represent the most frequent cause of isolated ATP synthase deficiency resulting in a severe mitochondrial disease presenting as neonatal encep...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/ddw295

    authors: Vrbacký M,Kovalčíková J,Chawengsaksophak K,Beck IM,Mráček T,Nůsková H,Sedmera D,Papoušek F,Kolář F,Sobol M,Hozák P,Sedlacek R,Houštěk J

    更新日期:2016-11-01 00:00:00

  • Mutant SPTLC1 dominantly inhibits serine palmitoyltransferase activity in vivo and confers an age-dependent neuropathy.

    abstract::Mutations in enzymes involved in sphingolipid metabolism and trafficking cause a variety of neurological disorders, but details of the molecular pathophysiology remain obscure. SPTLC1 encodes one subunit of serine palmitoyltransferase (SPT), the rate-limiting enzyme in sphingolipid synthesis. Mutations in SPTLC1 cause...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/ddi380

    authors: McCampbell A,Truong D,Broom DC,Allchorne A,Gable K,Cutler RG,Mattson MP,Woolf CJ,Frosch MP,Harmon JM,Dunn TM,Brown RH Jr

    更新日期:2005-11-15 00:00:00

  • Tsc/mTORC1 signaling in oocytes governs the quiescence and activation of primordial follicles.

    abstract::To maintain the female reproductive lifespan, the majority of ovarian primordial follicles are preserved in a quiescent state in order to provide ova for later reproductive life. However, the molecular mechanism that maintains the long quiescence of primordial follicles is poorly understood. Here we provide genetic ev...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/ddp483

    authors: Adhikari D,Zheng W,Shen Y,Gorre N,Hämäläinen T,Cooney AJ,Huhtaniemi I,Lan ZJ,Liu K

    更新日期:2010-02-01 00:00:00

  • Systemic transplantation of c-kit+ cells exerts a therapeutic effect in a model of amyotrophic lateral sclerosis.

    abstract::Amyotrophic lateral sclerosis (ALS) is a progressive, fatal, neurodegenerative disease characterized by the loss of motor neurons. Motor neuron degeneration is probably both a cell autonomous and a non-autonomous event. Therefore, manipulating the diseased microenvironment via non-neural cell replacement could be a th...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/ddq293

    authors: Corti S,Nizzardo M,Nardini M,Donadoni C,Salani S,Simone C,Falcone M,Riboldi G,Govoni A,Bresolin N,Comi GP

    更新日期:2010-10-01 00:00:00

  • The spinocerebellar ataxia type 1 protein, ataxin-1, has RNA-binding activity that is inversely affected by the length of its polyglutamine tract.

    abstract::Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disease caused by the expansion of a polyglutamine tract within the SCA1 product, ataxin-1. Previously, using transgenic mice, it was demonstrated that in order for a mutant allele of ataxin-1 to cause disease it must be transported to the...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/10.1.25

    authors: Yue S,Serra HG,Zoghbi HY,Orr HT

    更新日期:2001-01-01 00:00:00

  • SRY interference of normal regulation of the RET gene suggests a potential role of the Y-chromosome gene in sexual dimorphism in Hirschsprung disease.

    abstract::The Hirschsprung disease (HSCR) is a complex congenital disorder, arising from abnormalities in enteric nervous system (ENS) development. There is a gender disparity among the patients, with the male to female ratio as high as 5 : 1. Loss-of-function mutations of HSCR genes and haploinsufficiency of their gene product...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/ddu488

    authors: Li Y,Kido T,Garcia-Barcelo MM,Tam PK,Tabatabai ZL,Lau YF

    更新日期:2015-02-01 00:00:00

  • Asymptomatic homozygous hypobetalipoproteinemia associated with apolipoprotein B45.2.

    abstract::Familial hypobetalipoproteinemia is caused by apolipoprotein (apo) B gene mutations and is frequently associated with a truncated apo-B protein in the plasma. Homozygosity for mutations yielding a truncated apo-B is extremely rare; fewer than five true homozygotes have been described in the world's literature. These p...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/3.5.741

    authors: Young SG,Bihain B,Flynn LM,Sanan DA,Ayrault-Jarrier M,Jacotot B

    更新日期:1994-05-01 00:00:00

  • Fusion of the FUS and BBF2H7 genes in low grade fibromyxoid sarcoma.

    abstract::The FUS gene at 16p11 fuses with DDIT3 and ATF1 as the result of translocations with chromosome band 12q13 in myxoid liposarcoma and angiomatoid fibrous histiocytoma, respectively, and with ERG as the result of a t(16;21)(p11;q22) in acute myeloid leukemia. We here show that a t(7;16)(q33;p11) in two cases of low grad...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/ddg237

    authors: Storlazzi CT,Mertens F,Nascimento A,Isaksson M,Wejde J,Brosjo O,Mandahl N,Panagopoulos I

    更新日期:2003-09-15 00:00:00

  • Altered spatio-temporal dynamics of RNase H2 complex assembly at replication and repair sites in Aicardi-Goutières syndrome.

    abstract::Ribonuclease H2 plays an essential role for genome stability as it removes ribonucleotides misincorporated into genomic DNA by replicative polymerases and resolves RNA/DNA hybrids. Biallelic mutations in the genes encoding the three RNase H2 subunits cause Aicardi-Goutières syndrome (AGS), an early-onset inflammatory ...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/ddu319

    authors: Kind B,Muster B,Staroske W,Herce HD,Sachse R,Rapp A,Schmidt F,Koss S,Cardoso MC,Lee-Kirsch MA

    更新日期:2014-11-15 00:00:00

  • Glucosylceramide synthase inhibition with lucerastat lowers globotriaosylceramide and lysosome staining in cultured fibroblasts from Fabry patients with different mutation types.

    abstract::Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the GLA gene coding for α-galactosidase A (α-GalA). The deleterious mutations lead to accumulation of α-GalA substrates, including globotriaosylceramide (Gb3) and globotriaosylsphingosine. Progressive glycolipid storage results in cellular ...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/ddy248

    authors: Welford RWD,Mühlemann A,Garzotti M,Rickert V,Groenen PMA,Morand O,Üçeyler N,Probst MR

    更新日期:2018-10-01 00:00:00

  • Multi-stage genome-wide association study identifies new susceptibility locus for testicular germ cell tumour on chromosome 3q25.

    abstract::Recent genome-wide association studies (GWAS) and subsequent meta-analyses have identified over 25 SNPs at 18 loci, together accounting for >15% of the genetic susceptibility to testicular germ cell tumour (TGCT). To identify further common SNPs associated with TGCT, here we report a three-stage experiment, involving ...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/ddu511

    authors: Litchfield K,Sultana R,Renwick A,Dudakia D,Seal S,Ramsay E,Powell S,Elliott A,Warren-Perry M,Eeles R,Peto J,Kote-Jarai Z,Muir K,Nsengimana J,UKTCC.,Stratton MR,Easton DF,Bishop DT,Huddart RA,Rahman N,Turnbull C,

    更新日期:2015-02-15 00:00:00

  • Characterization of the repeat expansion size in C9orf72 in amyotrophic lateral sclerosis and frontotemporal dementia.

    abstract::Hexanucleotide repeat expansions within the C9orf72 gene are the most important genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The difficulty of developing a precise method to determine the expansion size has hampered the study of possible correlations between the hexanucleotid...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/ddt460

    authors: Dols-Icardo O,García-Redondo A,Rojas-García R,Sánchez-Valle R,Noguera A,Gómez-Tortosa E,Pastor P,Hernández I,Esteban-Pérez J,Suárez-Calvet M,Antón-Aguirre S,Amer G,Ortega-Cubero S,Blesa R,Fortea J,Alcolea D,Capdevila A,

    更新日期:2014-02-01 00:00:00