Abstract:
:Monogenic deficiency diseases provide unique opportunities to define the contributions of individual molecules to human physiology and to identify pathologies arising from their dysfunction. Here we describe a deficiency disease in two human siblings that presented with severe bleeding, frequent infections and osteopetrosis at an early age. These symptoms are consistent with but more severe than those reported for people with leukocyte adhesion deficiency III (LAD-III). Mechanistically, these symptoms arose from an inability to activate the integrins expressed on hematopoietic cells, including platelets and leukocytes. Immortalized lymphocyte cell lines isolated from the two individuals showed integrin activation defects. Several proteins previously implicated in integrin activation, including Ras-associated protein-1 (RAP1) and calcium and diacylglycerol-regulated guanine nucleotide exchange factor-1 (CALDAG-GEF1), were present and functional in these cell lines. The genetic basis for this disease was traced to a point mutation in the coding region of the KINDLIN3 (official gene symbol FERMT3) gene. When wild-type KINDLIN-3 was expressed in the immortalized lymphocytes, their integrins became responsive to activation signals. These results identify a genetic disease that severely compromises the health of the affected individuals and establish an essential role of KINDLIN-3 in integrin activation in humans. Furthermore, allogeneic bone marrow transplantation was shown to alleviate the symptoms of the disease.
journal_name
Nat Medjournal_title
Nature medicineauthors
Malinin NL,Zhang L,Choi J,Ciocea A,Razorenova O,Ma YQ,Podrez EA,Tosi M,Lennon DP,Caplan AI,Shurin SB,Plow EF,Byzova TVdoi
10.1038/nm.1917subject
Has Abstractpub_date
2009-03-01 00:00:00pages
313-8issue
3eissn
1078-8956issn
1546-170Xpii
nm.1917journal_volume
15pub_type
杂志文章相关文献
NATURE MEDICINE文献大全abstract::Smallpox was eradicated without an adequate understanding of how vaccination induced protection. In response to possible bioterrorism with smallpox, the UK government vaccinated approximately 300 health care workers with vaccinia virus (VACV) strain Lister. Antibody responses were analyzed using ELISA for multiple sur...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm1457
更新日期:2006-11-01 00:00:00
abstract::The identification of the genes associated with chromosomal translocation breakpoints has fundamentally changed understanding of the molecular basis of hematological malignancies. By contrast, the study of chromosomal deletions has been hampered by the large number of genes deleted and the complexity of their analysis...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm.2063
更新日期:2010-01-01 00:00:00
abstract::1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces clinical, biochemical and neuropathologic changes reminiscent of those which occur in idiopathic Parkinson's disease. 7-Nitroindazole (7-NI) is a relatively selective inhibitor of the neuronal isoform of nitric oxide synthase (NOS) that blocks MPTP neurotoxi...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm0996-1017
更新日期:1996-09-01 00:00:00
abstract::Viral replication and microbial translocation from the gut to the blood during HIV infection lead to hyperimmune activation, which contributes to the decline in CD4+ T cell numbers during HIV infection. Programmed death-1 (PD-1) and interleukin-10 (IL-10) are both upregulated during HIV infection. Blocking interaction...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm.2106
更新日期:2010-04-01 00:00:00
abstract::Transplantation of xenogeneic hepatocytes would provide a novel therapy for liver disease and would help to solve the problem of an insufficient supply of donor organs. We have tested whether xenogeneic cells infused into the liver could correct the metabolic defect in the Watanable heritable hyperlipidemic (WHHL) rab...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm0197-48
更新日期:1997-01-01 00:00:00
abstract::Emerging evidence supports the concept that T helper type 17 (T(H)17) cells, in addition to mediating autoimmunity, have key roles in mucosal immunity against extracellular pathogens. Interleukin-22 (IL-22) and IL-17A are both effector cytokines produced by the T(H)17 lineage, and both were crucial for maintaining loc...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm1710
更新日期:2008-03-01 00:00:00
abstract::Inducible nitric oxide synthase (iNOS) is a transcriptionally regulated enzyme that synthesizes nitric oxide from L-arginine that has a key role in the pathophysiology of systemic inflammation and sepsis. Transgenic animals with a null mutation for the iNOS gene are resistant to hypotension and death caused by Escheri...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm0596-581
更新日期:1996-05-01 00:00:00
abstract::Peroxisome proliferator-activated receptor-delta (PPAR-delta; also known as PPAR-beta) is expressed at high levels in colon tumors, but its contribution to colon cancer is unclear. We examined the role of PPAR-delta in colon carcinogenesis using PPAR-delta-deficient (Ppard(-/-)) mice. In both the Min mutant and chemic...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm1026
更新日期:2004-05-01 00:00:00
abstract::Physical function declines in old age, portending disability, increased health expenditures, and mortality. Cellular senescence, leading to tissue dysfunction, may contribute to these consequences of aging, but whether senescence can directly drive age-related pathology and be therapeutically targeted is still unclear...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/s41591-018-0092-9
更新日期:2018-08-01 00:00:00
abstract::In the version of this article originally published, there was an error in the legend for Extended Data Fig. 7. The legend for panel f was originally: "f, FACS analysis of IL7R-, CD62L- and CD45RA- expression on TRAC-1928ζ and TRAC-1XX CAR T cells at day 63 post CAR infusion (representative for at least n = 3 mice per...
journal_title:Nature medicine
pub_type: 已发布勘误
doi:10.1038/s41591-019-0360-3
更新日期:2019-03-01 00:00:00
abstract::It begins as a slowly expanding spot of light or similar visual disturbance, often accompanied by phantom noises and other sensory distortions. People who experience such 'auras' know all too well that these early warning signs will culminate in a head-splitting migraine, yet scientists have little idea what causes th...
journal_title:Nature medicine
pub_type: 新闻
doi:10.1038/nm0913-1083
更新日期:2013-09-01 00:00:00
abstract::Hematopoietic stem and progenitor cells (HSPC) are endowed with the role of generating and maintaining lifelong the extremely diverse pool of blood cells1. Clinically, transplantation of human HSPC from an allogeneic healthy donor or infusion of autologous gene-corrected HSPC can effectively replenish defective blood ...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/s41591-018-0195-3
更新日期:2018-11-01 00:00:00
abstract::Resistance to cancer therapies presents a significant clinical challenge. Recent studies have revealed intratumoral heterogeneity as a source of therapeutic resistance. However, it is unclear whether resistance is driven predominantly by pre-existing or de novo alterations, in part because of the resolution limits of ...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm.3841
更新日期:2015-05-01 00:00:00
abstract::Spinal bulbar muscular atrophy (SBMA) is a motor neuron disease caused by toxic gain of function of the androgen receptor (AR). Previously, we found that co-regulator binding through the activation function-2 (AF2) domain of AR is essential for pathogenesis, suggesting that AF2 may be a potential drug target for selec...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm.4500
更新日期:2018-05-01 00:00:00
abstract::A Correction to this paper has been published: https://doi.org/10.1038/s41591-020-01176-7. ...
journal_title:Nature medicine
pub_type: 已发布勘误
doi:10.1038/s41591-020-01176-7
更新日期:2020-12-01 00:00:00
abstract::We report the involvement of an evolutionarily conserved set of mycobacterial genes, the esx-3 region, in evasion of bacterial killing by innate immunity. Whereas high-dose intravenous infections of mice with the rapidly growing mycobacterial species Mycobacterium smegmatis bearing an intact esx-3 locus were rapidly l...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm.2420
更新日期:2011-09-04 00:00:00
abstract::Single-cell genomics is essential to chart tumor ecosystems. Although single-cell RNA-Seq (scRNA-Seq) profiles RNA from cells dissociated from fresh tumors, single-nucleus RNA-Seq (snRNA-Seq) is needed to profile frozen or hard-to-dissociate tumors. Each requires customization to different tissue and tumor types, posi...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/s41591-020-0844-1
更新日期:2020-05-01 00:00:00
abstract::A chimeric RNA/DNA oligonucleotide was constructed to induce a sequence mutation in the rat factor IX gene, resulting in prolonged coagulation. Oligonucleotides were targeted to hepatocytes in cell culture or in vivo by intravenous injection. Nucleotide conversion was both site-specific and dose-dependent. The mutated...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm0398-285
更新日期:1998-03-01 00:00:00
abstract::Epigenetic reprogramming is a critical process of pathological gene induction during cardiac hypertrophy and remodeling, but the underlying regulatory mechanisms remain to be elucidated. Here we identified a heart-enriched long noncoding (lnc)RNA, named cardiac-hypertrophy-associated epigenetic regulator (Chaer), whic...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm.4179
更新日期:2016-10-01 00:00:00
abstract::Given the associations between chronic inflammation and epithelial cancer, we studied susceptibility to skin carcinogenesis in mice deficient for the pro-inflammatory cytokine TNF-alpha (refs. 5,6). TNF-alpha(-/-) mice were resistant to development of benign and malignant skin tumors, whether induced by initiation wit...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/10552
更新日期:1999-07-01 00:00:00
abstract::Infections are thought to be important in the pathogenesis of many heart diseases. Coxsackievirus B3 (CVB3) has been linked to chronic dilated cardiomyopathy, a common cause of progressive heart disease, heart failure and sudden death. We show here that the sarcoma (Src) family kinase Lck (p56lck) is required for effi...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/74689
更新日期:2000-04-01 00:00:00
abstract::Cells that are deficient in homologous recombination, such as those that lack functional breast cancer-associated 1 (BRCA1) or BRCA2, are hypersensitive to inhibition of poly(ADP-ribose) polymerase (PARP). However, BRCA-deficient tumors represent only a small fraction of adult cancers, which might restrict the therape...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm.2377
更新日期:2011-06-26 00:00:00
abstract::Transforming growth factor beta 1 (TGF-beta 1) is a platelet-derived cytokine involved in both normal wound healing and scarring. We show that human platelets contain two pools of latent TGF-beta 1, which constitute more than 95% of the total TGF-beta assayed in whole platelets. During clotting, one pool, the large la...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm0995-932
更新日期:1995-09-01 00:00:00
abstract::Two big challenges of transplantation biology are controlling the reaction of the graft to the host after hematopoietic stem cell transplantation and preventing rejection of donor organs by the host. Raewyn Broady and Megan K. Levings discuss the first challenge, examining studies suggesting that statins might be help...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm1108-1155
更新日期:2008-11-01 00:00:00
abstract::Iron is an essential component of the erythrocyte protein hemoglobin and is crucial to oxygen transport in vertebrates. In the steady state, erythrocyte production is in equilibrium with erythrocyte removal. In various pathophysiological conditions, however, erythrocyte life span is compromised severely, which threate...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm.4146
更新日期:2016-08-01 00:00:00
abstract::The cycle of gallbladder filling and emptying controls the flow of bile into the intestine for digestion. Here we show that fibroblast growth factor-15, a hormone made by the distal small intestine in response to bile acids, is required for gallbladder filling. These studies demonstrate that gallbladder filling is act...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm1501
更新日期:2006-11-01 00:00:00
abstract::Sphingosine-1-phosphate (S1P) signaling influences bone metabolism, but its therapeutic potential in bone disorders has remained unexplored. We show that raising S1P levels in adult mice through conditionally deleting or pharmacologically inhibiting S1P lyase, the sole enzyme responsible for irreversibly degrading S1P...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/s41591-018-0005-y
更新日期:2018-05-01 00:00:00
abstract::Immunodeficiency is a barrier to successful vaccination in individuals with cancer and chronic infection. We performed a randomized phase 1/2 study in lymphopenic individuals after high-dose chemotherapy and autologous hematopoietic stem cell transplantation for myeloma. Combination immunotherapy consisting of a singl...
journal_title:Nature medicine
pub_type: 杂志文章,随机对照试验
doi:10.1038/nm1310
更新日期:2005-11-01 00:00:00
abstract::Exercise has numerous health-promoting effects in humans; however, individual responsiveness to exercise with regard to endurance or metabolic health differs markedly. This 'exercise resistance' is considered to be congenital, with no evident acquired causative factors. Here we show that the anti-oxidative hepatokine ...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm.4295
更新日期:2017-04-01 00:00:00
abstract::Cough accompanied by an increased sensitivity of the cough reflex is the most common symptom of inflammatory airway disease. This symptom is also frequently reported in patients receiving angiotensin-converting enzyme (ACE) inhibitors as therapy for heart failure or hypertension, although the underlying mechanism is u...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm0796-814
更新日期:1996-07-01 00:00:00