Abstract:
:We report 10 heterozygous mutations in the human insulin gene in 16 probands with neonatal diabetes. A combination of linkage and a candidate gene approach in a family with four diabetic members led to the identification of the initial INS gene mutation. The mutations are inherited in an autosomal dominant manner in this and two other small families whereas the mutations in the other 13 patients are de novo. Diabetes presented in probands at a median age of 9 weeks, usually with diabetic ketoacidosis or marked hyperglycemia, was not associated with beta cell autoantibodies, and was treated from diagnosis with insulin. The mutations are in critical regions of the preproinsulin molecule, and we predict that they prevent normal folding and progression of proinsulin in the insulin secretory pathway. The abnormally folded proinsulin molecule may induce the unfolded protein response and undergo degradation in the endoplasmic reticulum, leading to severe endoplasmic reticulum stress and potentially beta cell death by apoptosis. This process has been described in both the Akita and Munich mouse models that have dominant-acting missense mutations in the Ins2 gene, leading to loss of beta cell function and mass. One of the human mutations we report here is identical to that in the Akita mouse. The identification of insulin mutations as a cause of neonatal diabetes will facilitate the diagnosis and possibly, in time, treatment of this disorder.
journal_name
Proc Natl Acad Sci U S Aauthors
Støy J,Edghill EL,Flanagan SE,Ye H,Paz VP,Pluzhnikov A,Below JE,Hayes MG,Cox NJ,Lipkind GM,Lipton RB,Greeley SA,Patch AM,Ellard S,Steiner DF,Hattersley AT,Philipson LH,Bell GI,Neonatal Diabetes International Collaboradoi
10.1073/pnas.0707291104subject
Has Abstractpub_date
2007-09-18 00:00:00pages
15040-4issue
38eissn
0027-8424issn
1091-6490pii
0707291104journal_volume
104pub_type
杂志文章abstract::In a search for Polo-like kinase 1 (Plk1)-interacting proteins using a yeast two-hybrid system, we have identified histone acetyltransferase binding to the origin recognition complex 1 (Hbo1) as a potential Plk1 target. Here, we show that the interaction between Plk1 and Hbo1 is mitosis-specific and that Plk1 phosphor...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0712063105
更新日期:2008-02-12 00:00:00
abstract::Many changes have been described in the brains of Alzheimer's disease (AD) patients, including loss of neurons and formation of senile plaques and neurofibrillary tangles. The molecular mechanisms underlying these pathologies are unclear. Northern blot, dot-blot, and reverse transcription-coupled PCR analyses have dem...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.95.16.9620
更新日期:1998-08-04 00:00:00
abstract::By using the maximum likelihood method, we made a genome-wide comparison of the evolutionary rates in the lineages leading to the laboratory strain (S288c) and a wild strain (YJM789) of Saccharomyces cerevisiae and found that genes in the laboratory strain tend to evolve faster than in the wild strain. The pattern of ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0409159102
更新日期:2005-01-25 00:00:00
abstract::The suprachiasmatic nucleus (SCN) is the principal circadian pacemaker of mammals, coordinating daily rhythms of behavior and metabolism. Circadian timekeeping in SCN neurons revolves around transcriptional/posttranslational feedback loops, in which Period (Per) and Cryptochrome (Cry) genes are negatively regulated by...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1101767108
更新日期:2011-08-23 00:00:00
abstract::Kaposi's sarcoma-associated herpesvirus (KSHV), etiologically associated with Kaposi's sarcoma, uses integrins (α3β1, αVβ3, and αVβ5) and associated signaling to enter human dermal microvascular endothelial cells (HMVEC-d), an in vivo target of infection. KSHV infection activated c-Cbl, which induced the selective tra...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1119592109
更新日期:2012-05-08 00:00:00
abstract::Strongylocentrotus intermedius (A. Agassiz, 1863) is an economically important sea urchin inhabiting the northwest Pacific region of Asia. The northern Primorye (Sea of Japan) populations of S. intermedius consist of two sympatric morphological forms, "usual" (U) and "gray" (G). The two forms are significantly differe...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0807860105
更新日期:2008-10-21 00:00:00
abstract::Hydrogen bonds and their relative strengths in proteins are of importance for understanding protein structure and protein motions. The correct strength of such hydrogen bonds is experimentally known to vary greatly from approximately 5-6 kcal/mol for the isolated bond to approximately 0.5-1.5 kcal/mol for proteins in ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.2133366100
更新日期:2003-10-28 00:00:00
abstract::We examine the IFN-alpha/beta-independent activation of cellular transcription that constitutes an early antiviral response of cells against influenza A and B viruses, which cause widespread epidemics in humans. We show that influenza B virus induces the synthesis in human cells of several mature mRNAs encoded by gene...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.152327499
更新日期:2002-07-23 00:00:00
abstract::If a population (species) consists of n haploid lines (subpopulations) which reproduce asexually and each of which is subject to random extinction and subsequent replacement, it is shown that, at equilibrium in which mutational production of new alleles and their random extinction balance each other, the genetic diver...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.77.11.6710
更新日期:1980-11-01 00:00:00
abstract::The subventricular zone remains mitotically active throughout life in rodents. Studies with tritiated thymidine, which is incorporated into the DNA of mitotic cells, have revealed that the rodent subventricular zone produces neuroblasts that migrate toward the olfactory bulb along the rostral migratory stream. A simil...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.172403999
更新日期:2002-08-20 00:00:00
abstract::Charcot-Marie-Tooth disease type 4C (CMT4C) is an early-onset, autosomal recessive form of demyelinating neuropathy. The clinical manifestations include progressive scoliosis, delayed age of walking, muscular atrophy, distal weakness, and reduced nerve conduction velocity. The gene mutated in CMT4C disease, SH3TC2/KIA...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0905523106
更新日期:2009-10-13 00:00:00
abstract::We prove theorems on the structure of the fundamental group of a compact riemannian manifold of non-positive curvature. In particular, a conjecture of J. Wolf [J. Differential Geometry, 2, 421-446 (1968)] is proved. ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.67.2.509
更新日期:1970-10-01 00:00:00
abstract::Calcium/phospholipid-dependent protein kinase (protein kinase C, PKC) has been suggested to play a role in the sensitivity of gamma-aminobutyrate type A (GABAA) receptors to ethanol. We tested a line of null mutant mice that lacks the gamma isoform of PKC (PKC gamma) to determine the role of this brain-specific isoenz...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.92.9.3658
更新日期:1995-04-25 00:00:00
abstract::Sexual arousal is a dynamical, highly coordinated neurophysiological process that is often induced by visual stimuli. Numerous studies have proposed that the cognitive processing stage of responding to sexual stimuli is the first stage, in which sex differences occur, and the divergence between men and women has been ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章,meta分析
doi:10.1073/pnas.1904975116
更新日期:2019-07-30 00:00:00
abstract::Prion protein consists of an ensemble of glycosylated variants or glycoforms. The enzymes that direct oligosaccharide processing, and hence control the glycan profile for any given glycoprotein, are often exquisitely sensitive to other events taking place within the cell in which the glycoprotein is expressed. Alterat...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.96.23.13044
更新日期:1999-11-09 00:00:00
abstract::Homing endonucleases stimulate gene conversion by generating site-specific DNA double-strand breaks that are repaired by homologous recombination. These enzymes are potentially valuable tools for targeted gene correction and genome engineering. We have engineered a variant of the I-AniI homing endonuclease that nicks ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0810588106
更新日期:2009-03-31 00:00:00
abstract::A series of recombinant plasmids was generated in Escherichia coli in which the TEM beta-lactamase translocon (TnA) was inserted into the small plasmid RSF1010. RSF1010 is a 5.5 X 10(6) dalton nonconjugative plasmid which confers resistance to streptomycin and sulfonamide. The recombinant plasmids can be classified in...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.72.9.3623
更新日期:1975-09-01 00:00:00
abstract::Extracellular potassium concentration is actively maintained within narrow limits in all higher organisms. Slight variations in extracellular potassium levels can induce major alterations of essential physiological functions in excitable tissues. Here we describe that superfusion of cultured rat hippocampal neurones w...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.89.6.2466
更新日期:1992-03-15 00:00:00
abstract::Clear-cut inherited Mendelian traits, such as familial adenomatous polyposis or hereditary nonpolyposis colorectal cancer, account for <4% of colorectal cancers. Another 20% of all colorectal cancers are thought to occur in individuals with a significant inherited multifactorial susceptibility to colorectal cancer tha...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0407187101
更新日期:2004-11-09 00:00:00
abstract::It is suggested that differentiated embryonic cells have a high specificity of molecular constitution as regards the surface layers surrounding their cellular membranes. Correspondingly, specific interface energies may characterize the early contacts between different cell types. The question is raised whether the mor...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.67.1.156
更新日期:1970-09-01 00:00:00
abstract::Progressive myoclonus epilepsy of Univerricht-Lundborg type is a clinically defined entity among the progressive myoclonus epilepsies. It is an autosomal recessive disorder. The underlying biochemical defect is unknown. We used linkage analysis to localize the gene in 12 families with the aid of polymorphic DNA marker...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.88.9.3696
更新日期:1991-05-01 00:00:00
abstract::Several tissue culture cell lines that were transformed by a tumor virus have been found to react with an agglutinin, while under identical conditions their untransformed parent cell lines did not agglutinate. Since a short treatment of the parent cell line with low concentrations of proteases exposed the same aggluti...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.62.3.994
更新日期:1969-03-01 00:00:00
abstract::Rad51 is a highly conserved eukaryotic homolog of the prokaryotic recombination protein RecA, which has been shown to function in both recombinational repair of DNA damage and meiotic recombination in yeast. In primary murine B cells cultured with lipopolysaccharide (LPS) to stimulate heavy chain class switch recombin...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.93.19.10222
更新日期:1996-09-17 00:00:00
abstract::The origin recognition complex (ORC) binds sites from which DNA replication is initiated. We address ORC binding selectivity in vivo by mapping ∼52,000 ORC2 binding sites throughout the human genome. The ORC binding profile is broader than those of sequence-specific transcription factors, suggesting that ORC is not bo...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1609060113
更新日期:2016-08-16 00:00:00
abstract::Membrane proteins of cytotoxic T cells specifically reorganize to form an immunological synapse (IS) on interaction with their specific target. In this paper, we investigated the redistribution of Kv1.3 channels, which are the dominant voltage-gated potassium channels, in the plasma membrane of allogen-activated human...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0307421100
更新日期:2004-02-03 00:00:00
abstract::Patients with systemic lupus erythematosus (SLE) have accelerated atherosclerosis. The underlying mechanisms are poorly understood, and investigations have been hampered by the absence of animal models that reflect the human condition of generalized atherosclerosis and lupus. We addressed this problem by transferring ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0602311103
更新日期:2006-05-02 00:00:00
abstract::The ability of a specialized herbivore to overcome the chemical defense of a particular plant taxon not only makes it accessible as a food source but may also provide metabolites to be exploited for communication or chemical defense. Phyllotreta flea beetles are adapted to crucifer plants (Brassicales) that are defend...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1321781111
更新日期:2014-05-20 00:00:00
abstract::We have isolated several lines of rat embryo cells transformed by simian virus 40. All these lines are fully transformed with regard to saturation density and serum sensitivity, but they differ greatly in their anchorage dependence, as assayed by efficiency of plating in methyl cellulose suspension. This set of lines ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.71.12.4792
更新日期:1974-12-01 00:00:00
abstract::Selective culling in populations of most organisms is rank-order: individuals of low rank on a scale of potential fitnesses tend to be eliminated during early development, whereas surviving adults (whose number reflects the carrying capacity of the environment) are generally drawn from the distribution's upper end. Ha...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.86.6.2117
更新日期:1989-03-01 00:00:00
abstract::Charge transfer at metallo-molecular interfaces may be used to design multifunctional hybrids with an emergent magnetization that may offer an eco-friendly and tunable alternative to conventional magnets and devices. Here, we investigate the origin of the magnetism arising at these interfaces by using different techni...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1620216114
更新日期:2017-05-30 00:00:00