Abnormal type I collagen post-translational modification and crosslinking in a cyclophilin B KO mouse model of recessive osteogenesis imperfecta.


:Cyclophilin B (CyPB), encoded by PPIB, is an ER-resident peptidyl-prolyl cis-trans isomerase (PPIase) that functions independently and as a component of the collagen prolyl 3-hydroxylation complex. CyPB is proposed to be the major PPIase catalyzing the rate-limiting step in collagen folding. Mutations in PPIB cause recessively inherited osteogenesis imperfecta type IX, a moderately severe to lethal bone dysplasia. To investigate the role of CyPB in collagen folding and post-translational modifications, we generated Ppib-/- mice that recapitulate the OI phenotype. Knock-out (KO) mice are small, with reduced femoral areal bone mineral density (aBMD), bone volume per total volume (BV/TV) and mechanical properties, as well as increased femoral brittleness. Ppib transcripts are absent in skin, fibroblasts, femora and calvarial osteoblasts, and CyPB is absent from KO osteoblasts and fibroblasts on western blots. Only residual (2-11%) collagen prolyl 3-hydroxylation is detectable in KO cells and tissues. Collagen folds more slowly in the absence of CyPB, supporting its rate-limiting role in folding. However, treatment of KO cells with cyclosporine A causes further delay in folding, indicating the potential existence of another collagen PPIase. We confirmed and extended the reported role of CyPB in supporting collagen lysyl hydroxylase (LH1) activity. Ppib-/- fibroblast and osteoblast collagen has normal total lysyl hydroxylation, while increased collagen diglycosylation is observed. Liquid chromatography/mass spectrometry (LC/MS) analysis of bone and osteoblast type I collagen revealed site-specific alterations of helical lysine hydroxylation, in particular, significantly reduced hydroxylation of helical crosslinking residue K87. Consequently, underhydroxylated forms of di- and trivalent crosslinks are strikingly increased in KO bone, leading to increased total crosslinks and decreased helical hydroxylysine- to lysine-derived crosslink ratios. The altered crosslink pattern was associated with decreased collagen deposition into matrix in culture, altered fibril structure in tissue, and reduced bone strength. These studies demonstrate novel consequences of the indirect regulatory effect of CyPB on collagen hydroxylation, impacting collagen glycosylation, crosslinking and fibrillogenesis, which contribute to maintaining bone mechanical properties.


PLoS Genet


PLoS genetics


Cabral WA,Perdivara I,Weis M,Terajima M,Blissett AR,Chang W,Perosky JE,Makareeva EN,Mertz EL,Leikin S,Tomer KB,Kozloff KM,Eyre DR,Yamauchi M,Marini JC




Has Abstract


2014-06-26 00:00:00














  • Discordance of species trees with their most likely gene trees.

    abstract::Because of the stochastic way in which lineages sort during speciation, gene trees may differ in topology from each other and from species trees. Surprisingly, assuming that genetic lineages follow a coalescent model of within-species evolution, we find that for any species tree topology with five or more species, the...

    journal_title:PLoS genetics

    pub_type: 杂志文章


    authors: Degnan JH,Rosenberg NA

    更新日期:2006-05-01 00:00:00

  • A mutation in the SUV39H2 gene in Labrador Retrievers with hereditary nasal parakeratosis (HNPK) provides insights into the epigenetics of keratinocyte differentiation.

    abstract::Hereditary nasal parakeratosis (HNPK), an inherited monogenic autosomal recessive skin disorder, leads to crusts and fissures on the nasal planum of Labrador Retrievers. We performed a genome-wide association study (GWAS) using 13 HNPK cases and 23 controls. We obtained a single strong association signal on chromosome...

    journal_title:PLoS genetics

    pub_type: 杂志文章


    authors: Jagannathan V,Bannoehr J,Plattet P,Hauswirth R,Drögemüller C,Drögemüller M,Wiener DJ,Doherr M,Owczarek-Lipska M,Galichet A,Welle MM,Tengvall K,Bergvall K,Lohi H,Rüfenacht S,Linek M,Paradis M,Müller EJ,Roosje P,Leeb

    更新日期:2013-01-01 00:00:00

  • Cell size checkpoint control by the retinoblastoma tumor suppressor pathway.

    abstract::Size control is essential for all proliferating cells, and is thought to be regulated by checkpoints that couple cell size to cell cycle progression. The aberrant cell-size phenotypes caused by mutations in the retinoblastoma (RB) tumor suppressor pathway are consistent with a role in size checkpoint control, but indi...

    journal_title:PLoS genetics

    pub_type: 杂志文章


    authors: Fang SC,de los Reyes C,Umen JG

    更新日期:2006-10-13 00:00:00

  • A cautionary note on the use of unsupervised machine learning algorithms to characterise malaria parasite population structure from genetic distance matrices.

    abstract::Genetic surveillance of malaria parasites supports malaria control programmes, treatment guidelines and elimination strategies. Surveillance studies often pose questions about malaria parasite ancestry (e.g. how antimalarial resistance has spread) and employ statistical methods that characterise parasite population st...

    journal_title:PLoS genetics

    pub_type: 杂志文章


    authors: Watson JA,Taylor AR,Ashley EA,Dondorp A,Buckee CO,White NJ,Holmes CC

    更新日期:2020-10-09 00:00:00

  • A comprehensive genetic characterization of bacterial motility.

    abstract::We have developed a powerful experimental framework that combines competitive selection and microarray-based genetic footprinting to comprehensively reveal the genetic basis of bacterial behaviors. Application of this method to Escherichia coli motility identifies 95% of the known flagellar and chemotaxis genes, and r...

    journal_title:PLoS genetics

    pub_type: 杂志文章


    authors: Girgis HS,Liu Y,Ryu WS,Tavazoie S

    更新日期:2007-09-01 00:00:00

  • Mutations in MAB21L2 result in ocular Coloboma, microcornea and cataracts.

    abstract::Ocular coloboma results from abnormal embryonic development and is often associated with additional ocular and systemic features. Coloboma is a highly heterogeneous disorder with many cases remaining unexplained. Whole exome sequencing from two cousins affected with dominant coloboma with microcornea, cataracts, and s...

    journal_title:PLoS genetics

    pub_type: 杂志文章


    authors: Deml B,Kariminejad A,Borujerdi RH,Muheisen S,Reis LM,Semina EV

    更新日期:2015-02-26 00:00:00

  • Lifespan extension by preserving proliferative homeostasis in Drosophila.

    abstract::Regenerative processes are critical to maintain tissue homeostasis in high-turnover tissues. At the same time, proliferation of stem and progenitor cells has to be carefully controlled to prevent hyper-proliferative diseases. Mechanisms that ensure this balance, thus promoting proliferative homeostasis, are expected t...

    journal_title:PLoS genetics

    pub_type: 杂志文章


    authors: Biteau B,Karpac J,Supoyo S,Degennaro M,Lehmann R,Jasper H

    更新日期:2010-10-14 00:00:00

  • Myopathic lamin mutations cause reductive stress and activate the nrf2/keap-1 pathway.

    abstract::Mutations in the human LMNA gene cause muscular dystrophy by mechanisms that are incompletely understood. The LMNA gene encodes A-type lamins, intermediate filaments that form a network underlying the inner nuclear membrane, providing structural support for the nucleus and organizing the genome. To better understand t...

    journal_title:PLoS genetics

    pub_type: 杂志文章


    authors: Dialynas G,Shrestha OK,Ponce JM,Zwerger M,Thiemann DA,Young GH,Moore SA,Yu L,Lammerding J,Wallrath LL

    更新日期:2015-05-21 00:00:00

  • Only one isoform of Drosophila melanogaster CTP synthase forms the cytoophidium.

    abstract::CTP synthase is an essential enzyme that plays a key role in energy metabolism. Several independent studies have demonstrated that CTP synthase can form an evolutionarily conserved subcellular structure termed cytoophidium. In budding yeast, there are two isoforms of CTP synthase and both isoforms localize in cytoophi...

    journal_title:PLoS genetics

    pub_type: 杂志文章


    authors: Azzam G,Liu JL

    更新日期:2013-01-01 00:00:00

  • DNA damage as a consequence of NLR activation.

    abstract::DNA damage observed during plant immune responses is reported to be an intrinsic component of plant immunity. However, other immune responses may suppress DNA damage to maintain host genome integrity. Here, we show that immunity-related DNA damage can be abrogated by preventing cell death triggered by Nucleotide-bindi...

    journal_title:PLoS genetics

    pub_type: 杂志文章


    authors: Rodriguez E,Chevalier J,El Ghoul H,Voldum-Clausen K,Mundy J,Petersen M

    更新日期:2018-02-20 00:00:00

  • Gene co-expression network connectivity is an important determinant of selective constraint.

    abstract::While several studies have investigated general properties of the genetic architecture of natural variation in gene expression, few of these have considered natural, outbreeding populations. In parallel, systems biology has established that a general feature of biological networks is that they are scale-free, renderin...

    journal_title:PLoS genetics

    pub_type: 杂志文章


    authors: Mähler N,Wang J,Terebieniec BK,Ingvarsson PK,Street NR,Hvidsten TR

    更新日期:2017-04-13 00:00:00

  • Bayesian multiple logistic regression for case-control GWAS.

    abstract::Genetic variants in genome-wide association studies (GWAS) are tested for disease association mostly using simple regression, one variant at a time. Standard approaches to improve power in detecting disease-associated SNPs use multiple regression with Bayesian variable selection in which a sparsity-enforcing prior on ...

    journal_title:PLoS genetics

    pub_type: 杂志文章


    authors: Banerjee S,Zeng L,Schunkert H,Söding J

    更新日期:2018-12-31 00:00:00

  • Ribosome synthesis and MAPK activity modulate ionizing radiation-induced germ cell apoptosis in Caenorhabditis elegans.

    abstract::Synthesis of ribosomal RNA by RNA polymerase I (RNA pol I) is an elemental biological process and is key for cellular homeostasis. In a forward genetic screen in C. elegans designed to identify DNA damage-response factors, we isolated a point mutation of RNA pol I, rpoa-2(op259), that leads to altered rRNA synthesis a...

    journal_title:PLoS genetics

    pub_type: 杂志文章


    authors: Eberhard R,Stergiou L,Hofmann ER,Hofmann J,Haenni S,Teo Y,Furger A,Hengartner MO

    更新日期:2013-11-01 00:00:00

  • Conflict between noise and plasticity in yeast.

    abstract::Gene expression responds to changes in conditions but also stochastically among individuals. In budding yeast, both expression responsiveness across conditions ("plasticity") and cell-to-cell variation ("noise") have been quantified for thousands of genes and found to correlate across genes. It has been argued therefo...

    journal_title:PLoS genetics

    pub_type: 杂志文章


    authors: Lehner B

    更新日期:2010-11-04 00:00:00

  • A cis-regulatory signature for chordate anterior neuroectodermal genes.

    abstract::One of the striking findings of comparative developmental genetics was that expression patterns of core transcription factors are extraordinarily conserved in bilaterians. However, it remains unclear whether cis-regulatory elements of their target genes also exhibit common signatures associated with conserved embryoni...

    journal_title:PLoS genetics

    pub_type: 杂志文章


    authors: Haeussler M,Jaszczyszyn Y,Christiaen L,Joly JS

    更新日期:2010-04-15 00:00:00

  • Epigenetic regulation by heritable RNA.

    abstract::Genomic concepts are based on the assumption that phenotypes arise from the expression of genetic variants. However, the presence of non-Mendelian inheritance patterns provides a direct challenge to this view and suggests an important role for alternative mechanisms of gene regulation and inheritance. Over the past fe...

    journal_title:PLoS genetics

    pub_type: 杂志文章,评审


    authors: Liebers R,Rassoulzadegan M,Lyko F

    更新日期:2014-04-17 00:00:00

  • KRAB-zinc finger proteins and KAP1 can mediate long-range transcriptional repression through heterochromatin spreading.

    abstract::Krüppel-associated box domain-zinc finger proteins (KRAB-ZFPs) are tetrapod-specific transcriptional repressors encoded in the hundreds by the human genome. In order to explore their as yet ill-defined impact on gene expression, we developed an ectopic repressor assay, allowing the study of KRAB-mediated transcription...

    journal_title:PLoS genetics

    pub_type: 杂志文章


    authors: Groner AC,Meylan S,Ciuffi A,Zangger N,Ambrosini G,Dénervaud N,Bucher P,Trono D

    更新日期:2010-03-05 00:00:00

  • A single nucleotide polymorphism within the acetyl-coenzyme A carboxylase beta gene is associated with proteinuria in patients with type 2 diabetes.

    abstract::It has been suggested that genetic susceptibility plays an important role in the pathogenesis of diabetic nephropathy. A large-scale genotyping analysis of gene-based single nucleotide polymorphisms (SNPs) in Japanese patients with type 2 diabetes identified the gene encoding acetyl-coenzyme A carboxylase beta (ACACB)...

    journal_title:PLoS genetics

    pub_type: 杂志文章


    authors: Maeda S,Kobayashi MA,Araki S,Babazono T,Freedman BI,Bostrom MA,Cooke JN,Toyoda M,Umezono T,Tarnow L,Hansen T,Gaede P,Jorsal A,Ng DP,Ikeda M,Yanagimoto T,Tsunoda T,Unoki H,Kawai K,Imanishi M,Suzuki D,Shin HD,Pa

    更新日期:2010-02-12 00:00:00

  • Tcf7 is an important regulator of the switch of self-renewal and differentiation in a multipotential hematopoietic cell line.

    abstract::A critical problem in biology is understanding how cells choose between self-renewal and differentiation. To generate a comprehensive view of the mechanisms controlling early hematopoietic precursor self-renewal and differentiation, we used systems-based approaches and murine EML multipotential hematopoietic precursor...

    journal_title:PLoS genetics

    pub_type: 杂志文章


    authors: Wu JQ,Seay M,Schulz VP,Hariharan M,Tuck D,Lian J,Du J,Shi M,Ye Z,Gerstein M,Snyder MP,Weissman S

    更新日期:2012-01-01 00:00:00

  • The NADPH metabolic network regulates human αB-crystallin cardiomyopathy and reductive stress in Drosophila melanogaster.

    abstract::Dominant mutations in the alpha-B crystallin (CryAB) gene are responsible for a number of inherited human disorders, including cardiomyopathy, skeletal muscle myopathy, and cataracts. The cellular mechanisms of disease pathology for these disorders are not well understood. Among recent advances is that the disease sta...

    journal_title:PLoS genetics

    pub_type: 杂志文章


    authors: Xie HB,Cammarato A,Rajasekaran NS,Zhang H,Suggs JA,Lin HC,Bernstein SI,Benjamin IJ,Golic KG

    更新日期:2013-06-01 00:00:00

  • Rfx2 Stabilizes Foxj1 Binding at Chromatin Loops to Enable Multiciliated Cell Gene Expression.

    abstract::Cooperative transcription factor binding at cis-regulatory sites in the genome drives robust eukaryotic gene expression, and many such sites must be coordinated to produce coherent transcriptional programs. The transcriptional program leading to motile cilia formation requires members of the DNA-binding forkhead (Fox)...

    journal_title:PLoS genetics

    pub_type: 杂志文章


    authors: Quigley IK,Kintner C

    更新日期:2017-01-19 00:00:00

  • Oligoasthenoteratozoospermia and infertility in mice deficient for miR-34b/c and miR-449 loci.

    abstract::Male fertility requires the continuous production of high quality motile spermatozoa in abundance. Alterations in all three metrics cause oligoasthenoteratozoospermia, the leading cause of human sub/infertility. Post-mitotic spermatogenesis inclusive of several meiotic stages and spermiogenesis (terminal spermatozoa d...

    journal_title:PLoS genetics

    pub_type: 杂志文章


    authors: Comazzetto S,Di Giacomo M,Rasmussen KD,Much C,Azzi C,Perlas E,Morgan M,O'Carroll D

    更新日期:2014-10-16 00:00:00

  • Calcium-responsive transactivator (CREST) toxicity is rescued by loss of PBP1/ATXN2 function in a novel yeast proteinopathy model and in transgenic flies.

    abstract::Proteins associated with familial neurodegenerative disease often aggregate in patients' neurons. Several such proteins, e.g. TDP-43, aggregate and are toxic when expressed in yeast. Deletion of the ATXN2 ortholog, PBP1, reduces yeast TDP-43 toxicity, which led to identification of ATXN2 as an amyotrophic lateral scle...

    journal_title:PLoS genetics

    pub_type: 杂志文章


    authors: Park S,Park SK,Watanabe N,Hashimoto T,Iwatsubo T,Shelkovnikova TA,Liebman SW

    更新日期:2019-08-07 00:00:00

  • The genetic architecture of the genome-wide transcriptional response to ER stress in the mouse.

    abstract::Endoplasmic reticulum (ER) stress occurs when misfolded proteins accumulate in the ER. The cellular response to ER stress involves complex transcriptional and translational changes, important to the survival of the cell. ER stress is a primary cause and a modifier of many human diseases. A first step to understanding ...

    journal_title:PLoS genetics

    pub_type: 杂志文章


    authors: Chow CY,Wang X,Riccardi D,Wolfner MF,Clark AG

    更新日期:2015-02-04 00:00:00

  • Comparative analysis of regulatory elements between Escherichia coli and Klebsiella pneumoniae by genome-wide transcription start site profiling.

    abstract::Genome-wide transcription start site (TSS) profiles of the enterobacteria Escherichia coli and Klebsiella pneumoniae were experimentally determined through modified 5' RACE followed by deep sequencing of intact primary mRNA. This identified 3,746 and 3,143 TSSs for E. coli and K. pneumoniae, respectively. Experimental...

    journal_title:PLoS genetics

    pub_type: 杂志文章


    authors: Kim D,Hong JS,Qiu Y,Nagarajan H,Seo JH,Cho BK,Tsai SF,Palsson BØ

    更新日期:2012-01-01 00:00:00

  • Genome-wide association study and gene expression analysis identifies CD84 as a predictor of response to etanercept therapy in rheumatoid arthritis.

    abstract::Anti-tumor necrosis factor alpha (anti-TNF) biologic therapy is a widely used treatment for rheumatoid arthritis (RA). It is unknown why some RA patients fail to respond adequately to anti-TNF therapy, which limits the development of clinical biomarkers to predict response or new drugs to target refractory cases. To u...

    journal_title:PLoS genetics

    pub_type: 杂志文章,meta分析


    authors: Cui J,Stahl EA,Saevarsdottir S,Miceli C,Diogo D,Trynka G,Raj T,Mirkov MU,Canhao H,Ikari K,Terao C,Okada Y,Wedrén S,Askling J,Yamanaka H,Momohara S,Taniguchi A,Ohmura K,Matsuda F,Mimori T,Gupta N,Kuchroo M,Morg

    更新日期:2013-03-01 00:00:00

  • Inhibition of the Smc5/6 complex during meiosis perturbs joint molecule formation and resolution without significantly changing crossover or non-crossover levels.

    abstract::Meiosis is a specialized cell division used by diploid organisms to form haploid gametes for sexual reproduction. Central to this reductive division is repair of endogenous DNA double-strand breaks (DSBs) induced by the meiosis-specific enzyme Spo11. These DSBs are repaired in a process called homologous recombination...

    journal_title:PLoS genetics

    pub_type: 杂志文章


    authors: Lilienthal I,Kanno T,Sjögren C

    更新日期:2013-11-01 00:00:00

  • Physiological IRE-1-XBP-1 and PEK-1 signaling in Caenorhabditis elegans larval development and immunity.

    abstract::Endoplasmic reticulum (ER) stress activates the Unfolded Protein Response, a compensatory signaling response that is mediated by the IRE-1, PERK/PEK-1, and ATF-6 pathways in metazoans. Genetic studies have implicated roles for UPR signaling in animal development and disease, but the function of the UPR under physiolog...

    journal_title:PLoS genetics

    pub_type: 杂志文章


    authors: Richardson CE,Kinkel S,Kim DH

    更新日期:2011-11-01 00:00:00

  • The CFTR Met 470 allele is associated with lower birth rates in fertile men from a population isolate.

    abstract::Although little is known about the role of the cystic fibrosis transmembrane regulator (CFTR) gene in reproductive physiology, numerous variants in this gene have been implicated in etiology of male infertility due to congenital bilateral absence of the vas deferens (CBAVD). Here, we studied the fertility effects of t...

    journal_title:PLoS genetics

    pub_type: 杂志文章


    authors: Kosova G,Pickrell JK,Kelley JL,McArdle PF,Shuldiner AR,Abney M,Ober C

    更新日期:2010-06-03 00:00:00

  • New microRNAs in Drosophila--birth, death and cycles of adaptive evolution.

    abstract::The origin and evolution of new microRNAs (miRNAs) is important because they can impact the transcriptome broadly. As miRNAs can potentially emerge constantly and rapidly, their rates of birth and evolution have been extensively debated. However, most new miRNAs identified appear not to be biologically significant. Af...

    journal_title:PLoS genetics

    pub_type: 杂志文章


    authors: Lyu Y,Shen Y,Li H,Chen Y,Guo L,Zhao Y,Hungate E,Shi S,Wu CI,Tang T

    更新日期:2014-01-01 00:00:00