scholarly journals Biallelic CXCR2 loss-of-function mutations define a distinct congenital neutropenia entity

Haematologica ◽  
2021 ◽  
Author(s):  
Viviana Marin-Esteban ◽  
Jenny Youn ◽  
Blandine Beaupain ◽  
Agnieszka Jaracz-Ros ◽  
Vincent Barlogis ◽  
...  

Not available.

2011 ◽  
Vol 193 (3) ◽  
pp. 465-473 ◽  
Author(s):  
Peter J. Cavnar ◽  
Erwin Berthier ◽  
David J. Beebe ◽  
Anna Huttenlocher

Kostmann disease is an inherited severe congenital neutropenia syndrome associated with loss-of-function mutations in an adaptor protein HS1-associated protein X-1 (Hax1). How Hax1 regulates neutrophil function remains largely unknown. In this paper, we use ribonucleic acid interference to deplete Hax1 in the neutrophil-like cell line PLB-985 and identify Hax1 as a negative regulator of integrin-mediated adhesion and chemotaxis. Using microfluidics, we show that depletion of Hax1 impairs neutrophil uropod detachment and directed migration. Hax1-deficient cells also display increased integrin-mediated adhesion and reduced RhoA activity. Moreover, depletion of RhoA induces increased neutrophil adhesion and impaired migration, suggesting that Hax1 regulates neutrophil adhesion and chemotaxis through RhoA. Accordingly, activation of RhoA is sufficient to rescue adhesion of Hax1-deficient neutrophils. Together, our findings identify Hax1 as a novel regulator of neutrophil uropod detachment and chemotaxis through RhoA.


Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1025-1025
Author(s):  
Alexa Triot ◽  
Päivi M Järvinen ◽  
Juan I. Arostegui ◽  
Tomas Racek ◽  
Jacek Puchalka ◽  
...  

Abstract Severe congenital neutropenia (SCN) is a heterogeneous group of disorders characterized by defective production and viability of neutrophil granulocytes and predisposition to life-threatening bacterial infections. Currently, OMIM lists five defined monogenic SCN: SCN1 ELANE, SCN2 GFI1, SCN3 HAX1, SCN4 G6PC3. Here, we describe a novel SCN subtype (SCN6) caused by recessively-inherited loss-of-function mutations in the gene encoding the granulocyte colony-stimulating receptor (CSF3R). We have identified four affected children in two distinct families. Family A had a homozygous missense mutation in close proximity of the highly conserved WSXWS motif (c.922T, p.Arg308Cys) and family B had two compound heterozygous small deletions provoking frameshift mutations (p.Gly316fs and p.Gly415fs). Mutated G-CSFR p.Arg308Cys protein was characterized by perturbed N-glycosylation and aberrant localization to cell surface. G-CSF induced phosphorylation of STAT3 and STAT5 was greatly diminished. In contrast to other SCN subtypes, all patients had morphological evidence of full myeloid cell maturation in bone marrow. However, none of the patients responded to granulocyte colony-stimulating growth factor (GCSF) treatment in vivo, confirming aberrant GCSF-receptor dependent signaling. Our studies highlight the genetic and morphological variability of SCN and provide evidence both for functional importance and redundancy of G-CSFR-mediated signaling in human granulopoiesis. Disclosures: No relevant conflicts of interest to declare.


Blood ◽  
2015 ◽  
Vol 126 (15) ◽  
pp. 1865-1867 ◽  
Author(s):  
Maksim Klimiankou ◽  
Olga Klimenkova ◽  
Murat Uenalan ◽  
Alexander Zeidler ◽  
Sabine Mellor-Heineke ◽  
...  

2005 ◽  
Vol 41 ◽  
pp. 15-30 ◽  
Author(s):  
Helen C. Ardley ◽  
Philip A. Robinson

The selectivity of the ubiquitin–26 S proteasome system (UPS) for a particular substrate protein relies on the interaction between a ubiquitin-conjugating enzyme (E2, of which a cell contains relatively few) and a ubiquitin–protein ligase (E3, of which there are possibly hundreds). Post-translational modifications of the protein substrate, such as phosphorylation or hydroxylation, are often required prior to its selection. In this way, the precise spatio-temporal targeting and degradation of a given substrate can be achieved. The E3s are a large, diverse group of proteins, characterized by one of several defining motifs. These include a HECT (homologous to E6-associated protein C-terminus), RING (really interesting new gene) or U-box (a modified RING motif without the full complement of Zn2+-binding ligands) domain. Whereas HECT E3s have a direct role in catalysis during ubiquitination, RING and U-box E3s facilitate protein ubiquitination. These latter two E3 types act as adaptor-like molecules. They bring an E2 and a substrate into sufficiently close proximity to promote the substrate's ubiquitination. Although many RING-type E3s, such as MDM2 (murine double minute clone 2 oncoprotein) and c-Cbl, can apparently act alone, others are found as components of much larger multi-protein complexes, such as the anaphase-promoting complex. Taken together, these multifaceted properties and interactions enable E3s to provide a powerful, and specific, mechanism for protein clearance within all cells of eukaryotic organisms. The importance of E3s is highlighted by the number of normal cellular processes they regulate, and the number of diseases associated with their loss of function or inappropriate targeting.


2004 ◽  
Vol 71 ◽  
pp. 193-202 ◽  
Author(s):  
David R Brown

Prion diseases, also referred to as transmissible spongiform encephalopathies, are characterized by the deposition of an abnormal isoform of the prion protein in the brain. However, this aggregated, fibrillar, amyloid protein, termed PrPSc, is an altered conformer of a normal brain glycoprotein, PrPc. Understanding the nature of the normal cellular isoform of the prion protein is considered essential to understanding the conversion process that generates PrPSc. To this end much work has focused on elucidation of the normal function and activity of PrPc. Substantial evidence supports the notion that PrPc is a copper-binding protein. In conversion to the abnormal isoform, this Cu-binding activity is lost. Instead, there are some suggestions that the protein might bind other metals such as Mn or Zn. PrPc functions currently under investigation include the possibility that the protein is involved in signal transduction, cell adhesion, Cu transport and resistance to oxidative stress. Of these possibilities, only a role in Cu transport and its action as an antioxidant take into consideration PrPc's Cu-binding capacity. There are also more published data supporting these two functions. There is strong evidence that during the course of prion disease, there is a loss of function of the prion protein. This manifests as a change in metal balance in the brain and other organs and substantial oxidative damage throughout the brain. Thus prions and metals have become tightly linked in the quest to understand the nature of transmissible spongiform encephalopathies.


2008 ◽  
Vol 13 (2) ◽  
pp. 5-5

Abstract Although most chapters in the AMA Guides to the Evaluation of Permanent Impairment (AMA Guides), Sixth Edition, instruct evaluators to perform impairment ratings by first assigning a diagnosis-based class and then assigning a grade within that class, Chapter 13, The Central and Peripheral Nervous System, continues to use a methodology similar to that of the fifth edition. The latter was criticized for duplicating materials that were presented in other chapters and for producing different ratings, so the revision of Chapter 13 attempts to maintain consistency between this chapter and those that address mental and behavioral disorders, loss of function in upper and lower extremities, loss of bowel control, and bladder and sexual function. A table titled Summary of Chapters Used to Rate Various Neurologic Disorders directs physicians to the relevant chapters (ie, instead of Chapter 13) to consult in rating neurologic disorders; the extensive list of conditions that should be addressed in other chapters includes but is not limited to radiculopathy, plexus injuries and other plexopathies, focal neuropathy, complex regional pain syndrome, visual and vestibular disorders, and a range of primary mood, anxiety, and psychotic disorders. The article comments in detail on sections of this chapter, identifies changes in the sixth edition, and provide guidance regarding use of the new edition, resulting in less duplication and greater consistency.


1998 ◽  
Vol 3 (4) ◽  
pp. 6-6
Author(s):  
Marc T. Taylor

Abstract This article discusses two important cases that involve the AMA Guides to the Evaluation of Permanent Impairment (AMA Guides). First, in Vargas v Industrial Com’n of Arizona, a claimant had a pre-existing non–work-related injury to his right knee as well as a work-related injury, and the issue was apportionment of the pre-existing injury. The court held that, under Arizona's statute, the impairment from the pre-existing injury should be subtracted from the current work-related impairment. In the second case, Colorado courts addressed the issue of apportionment in a workers’ compensation claim in which the pre-existing injury was asymptomatic at the time of the work-related injury (Askey v Industrial Claim Appeals Office). In this case, the court held that the worker's benefits should not be reduced to account for an asymptomatic pre-existing condition that could not be rated accurately using the AMA Guides. The AMA Guides bases impairment ratings on anatomic or physiologic loss of function, and if an examinee presents with two or more sequential injuries and calculable impairments, the AMA Guides can be used to apportion between pre-existing and subsequent impairments. Courts often use the AMA Guides to decide statutorily determined benefits and are subject to interpretation by courts and administrative bodies whose interpretations may vary from state to state.


2010 ◽  
Vol 15 (3) ◽  
pp. 1-7
Author(s):  
Richard T. Katz

Abstract This article addresses some criticisms of the AMA Guides to the Evaluation of Permanent Impairment (AMA Guides) by comparing previously published outcome data from a group of complete spinal cord injury (SCI) persons with impairment ratings for a corresponding level of injury calculated using the AMA Guides, Sixth Edition. Results of the comparison show that impairment ratings using the sixth edition scale poorly with the level of impairments of activities of daily living (ADL) in SCI patients as assessed by the Functional Independence Measure (FIM) motor scale and the extended FIM motor scale. Because of the combinations of multiple impairments, the AMA Guides potentially overrates the impairment of paraplegics compared with that of quadriplegics. The use and applicability of the Combined Values formula should be further investigated, and complete loss of function of two upper extremities seems consistent with levels of quadriplegia using the SCI model. Some aspects of the AMA Guides contain inconsistencies. The concept of diminishing impairment values is not easily translated between specific losses of function per organ system and “overall” loss of ADLs involving multiple organ systems, and the notion of “catastrophic thresholds” involving multiple organ systems may support the understanding that variations in rating may exist in higher rating cases such as those that involve an SCI.


1998 ◽  
Vol 3 (5) ◽  
pp. 8-10
Author(s):  
Robert L. Knobler ◽  
Charles N. Brooks ◽  
Leon H. Ensalada ◽  
James B. Talmage ◽  
Christopher R. Brigham

Abstract The author of the two-part article about evaluating reflex sympathetic dystrophy (RSD) responds to criticisms that a percentage impairment score may not adequately reflect the disability of an individual with RSD. The author highlights the importance of recognizing the difference between impairment and disability in the AMA Guides to the Evaluation of Permanent Impairment (AMA Guides): impairment is the loss, loss of use, or derangement of any body part, system, or function; disability is a decrease in or the loss or absence of the capacity to meet personal, social, or occupational demands or to meet statutory or regulatory requirements because of an impairment. The disparity between impairment and disability can be encountered in diverse clinical scenarios. For example, a person's ability to resume occupational activities following a major cardiac event depends on medical, social, and psychological factors, but nonmedical factors appear to present the greatest impediment and many persons do not resume work despite significant improvements in functional capacity. A key requirement according to the AMA Guides is objective documentation, and the author agrees that when physicians consider the disability evaluation of people, more issues than those relating to the percentage loss of function should be considered. More study of the relationships among impairment, disability, and quality of life in patients with RSD are required.


2011 ◽  
Vol 49 (08) ◽  
Author(s):  
N Milosevic ◽  
S Ripka ◽  
H Griesmann ◽  
B Kuehnemuth ◽  
M Buchholz ◽  
...  
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