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1.
J Inherit Metab Dis ; 44(6): 1441-1452, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34389986

RESUMO

Fucosylation is essential for intercellular and intracellular recognition, cell-cell interaction, fertilization, and inflammatory processes. Only five types of congenital disorders of glycosylation (CDG) related to an impaired fucosylation have been described to date: FUT8-CDG, FCSK-CDG, POFUT1-CDG SLC35C1-CDG, and the only recently described GFUS-CDG. This review summarizes the clinical findings of all hitherto known 25 patients affected with those defects with regard to their pathophysiology and genotype. In addition, we describe five new patients with novel variants in the SLC35C1 gene. Furthermore, we discuss the efficacy of fucose therapy approaches within the different defects.


Assuntos
Defeitos Congênitos da Glicosilação/tratamento farmacológico , Defeitos Congênitos da Glicosilação/genética , Fucose/uso terapêutico , Proteínas de Transporte de Monossacarídeos/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Glicoproteínas , Glicosilação , Humanos , Lactente , Masculino , Resultado do Tratamento , Adulto Jovem
2.
STAR Protoc ; 4(1): 102073, 2023 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-36853722

RESUMO

Mitochondrial metabolism is critical in hematopoietic stem cell maintenance and differentiation. Here, we present a step-by-step protocol to efficiently differentiate human induced pluripotent stem cells into myeloid progenitors by a robust feeder- and serum-free system. Furthermore, we provide a protocol to subsequently assess mitochondrial function in iPSC-derived myeloid progenitors. We comprehensively describe a protocol to analyze and to quantify key parameters of mitochondrial respiration of iPSC-derived myeloid progenitors by the Seahorse XFe96 Analyzer. Additionally, our protocol includes extensive troubleshooting suggestions. For complete details on the use and execution of this protocol, please refer to Fan et al. (2022).1.


Assuntos
Células-Tronco Pluripotentes Induzidas , Humanos , Células-Tronco Hematopoéticas , Células Progenitoras Mieloides/metabolismo , Respiração , Mitocôndrias/metabolismo
3.
J Clin Invest ; 132(9)2022 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-35499078

RESUMO

The relevance of molecular mechanisms governing mitochondrial proteostasis to the differentiation and function of hematopoietic and immune cells is largely elusive. Through dissection of the network of proteins related to HCLS1-associated protein X-1, we defined a potentially novel functional CLPB/HAX1/(PRKD2)/HSP27 axis with critical importance for the differentiation of neutrophil granulocytes and, thus, elucidated molecular and metabolic mechanisms underlying congenital neutropenia in patients with HAX1 deficiency as well as bi- and monoallelic mutations in CLPB. As shown by stable isotope labeling by amino acids in cell culture (SILAC) proteomics, CLPB and HAX1 control the balance of mitochondrial protein synthesis and persistence crucial for proper mitochondrial function. Impaired mitochondrial protein dynamics are associated with decreased abundance of the serine-threonine kinase PRKD2 and HSP27 phosphorylated on serines 78 and 82. Cellular defects in HAX1-/- cells can be functionally reconstituted by HSP27. Thus, mitochondrial proteostasis emerges as a critical molecular and metabolic mechanism governing the differentiation and function of neutrophil granulocytes.


Assuntos
Neutrófilos , Proteostase , Proteínas Adaptadoras de Transdução de Sinal/genética , Granulócitos/metabolismo , Proteínas de Choque Térmico HSP27/metabolismo , Humanos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Mutação , Neutrófilos/metabolismo
4.
Expert Rev Hematol ; 14(10): 945-960, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34486458

RESUMO

INTRODUCTION: Neutropenia is a relatively common finding in medical practice and the medical approach requires a gradual and pertinent diagnostic procedure as well as adapted management. AREAS COVERED: The area of chronic neutropenia remains fragmented between diverse diseases or situations. Here physicians involved in different aspects of chronic neutropenia gather both the data from medical literature till the end of May 2021 and their experience to offer a global approach for the diagnosis of chronic neutropenia as well as their medical care. EXPERT OPINION: In most cases, the neutropenia is transient, frequently related to a viral infection, and not harmful. However, neutropenia can be chronic (i.e. >3 months) and related to a number of etiologies, some clinically benign, such as so-called 'ethnic' neutropenia. Autoimmune neutropenia is the common form in young children, whereas idiopathic/immune neutropenia is a frequent etiology in young females. Inherited neutropenia (or congenital neutropenia) is exceptional, with approximately 30 new cases per 106 births and 30 known subtypes. Such patients have a high risk of invasive bacterial infections, and oral infections. Supportive therapy, which is primarily based on daily administration of an antibiotic prophylaxis and/or treatment with granulocyte-colony stimulating factor (G-CSF), contributes to avoiding recurrent infections.


Assuntos
Infecções Bacterianas , Neutropenia , Antibioticoprofilaxia/efeitos adversos , Criança , Pré-Escolar , Síndrome Congênita de Insuficiência da Medula Óssea , Feminino , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Neutropenia/diagnóstico , Neutropenia/etiologia , Neutropenia/terapia
5.
Cardiovasc Res ; 97(3): 454-63, 2013 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-23241315

RESUMO

AIMS: Future cardiac repair strategies will require a profound understanding of the principles underlying cardiovascular differentiation. Owing to its extracorporal and rapid development, Xenopus laevis provides an ideal experimental system to address these issues in vivo. Whereas mammalian MesP1 is currently regarded as the earliest marker for the cardiovascular system, several MesP1-related factors from Xenopus-mespa, mespb, and mespo-have been assigned only to somitogenesis so far. We, therefore, analysed these genes comparatively for potential contributions to cardiogenesis. METHODS AND RESULTS: RNA in situ hybridizations revealed a novel anterior expression domain exclusively occupied by mespa during gastrulation, which precedes the prospective heart field. Correspondingly, when overexpressed mespa most strongly induced cardiac markers in vivo as well as ex vivo. Transference to murine embryonic stem (ES) cells and subsequent FACS analyses for Flk-1 and Troponin I confirmed the high potential of mespa as a cardiac inducer. In vivo, Morpholino-based knockdown of mespa protein led to a dramatic loss of pro-cardiac and sarcomeric markers, which could be rescued either by mespa itself or human MesP1, but neither by mespb nor mespo. Epistatic analysis positioned mespa upstream of mespo and mespb, and revealed positive autoregulation for mespa at the time of its induction. CONCLUSIONS: Our findings contribute to the understanding of conserved events initiating vertebrate cardiogenesis. We identify mespa as functional amphibian homologue of mammalian MesP1. These results will enable the dissection of cardiac specification from the very beginning in the highly versatile Xenopus system.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/fisiologia , Diferenciação Celular/fisiologia , Coração/embriologia , Miócitos Cardíacos/citologia , Proteínas de Xenopus/fisiologia , Xenopus laevis/embriologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Células Cultivadas , Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Coração/fisiologia , Camundongos , Modelos Animais , Morfolinos/farmacologia , Miócitos Cardíacos/fisiologia , Proteínas de Xenopus/genética , Xenopus laevis/fisiologia
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