JAGN1 deficiency causes aberrant myeloid cell homeostasis and congenital neutropenia

Boztuğ, Kaan; Järvinen, Päivi; Salzer, Elisabeth; Raček, Tomáš; Mönch, Sebastian; Garncarz, Wojciech; Gertz, E. Michael; Schäffer, Alejandro A.; Antonopoulos, Aristotelis; Haslam, Stuart M.; Schieck, Lena; Puchałka, Jacek; Diestelhorst, Jana; Appaswamy, Giridharan; Lescoeur, Brigitte; Giambruno, Roberto; Bigenzahn, Johannes W.; Elling, Ulrich; Pfeifer, Dietmar; Conde, Cecilia Domínguez; Albert, Michael H.; Welte, Karl; Brandes, Gudrun; Sherkat, Roya; Bosch, Jutte van der Werff ten; Rezaei, Nima; Etzioni, Amos; Bellanné‐Chantelot, Christine; Superti‐Furga, Giulio; Penninger, Josef; Bennett, Keiryn L.; Blume, Julia von; Dell, Anne; Donadieu, Jean; Klein, Christoph

doi:10.1038/ng.3069

Cited by 118 publications

(125 citation statements)

References 51 publications

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“…JAGN-1 deficiency which has been very recently identified is also one of the causes of severe neutropenia. It has autosomal recessive inheritance and adequate increase in the neutrophil count is not found with G-CSF treatment (20). Since RUNX1 and CSF3R mutations among congenital neutropenias carry a potential for leukemia, G-CSF should be used carefully in patients with these mutations (21).…”

Section: Innovations In Neutropeniamentioning

confidence: 99%

Approach to the patient with neutropenia in childhood

Çelkan

Koç

2015

Turk Pediatri Ars

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Neutrophils have an important role in host defense and acute inflammation. It is well known that susceptibility to infection increases when the neutrophil count is low. Neutropenia were classified as mild, moderate and severe according to the neutrophil counts, or acute and chronic depending on the duration of neutropenia, or congenital and acquired according to the mechanism. The patients with neutropenia are clinically different due to underlying mechanism, they have life-threatening infections or no infection may be observed. The most common cause of acquired neutropenia is viral infection, followed by drugs and autoimmune neutropenia. Congenital neutropenia are usually diagnosed by acute and life-threatening invasive bacterial and fungal infections. Immune system disorders and other systemic abnormalities may be accompanied or not. Recent years, novel single gen defects causing congenital neutropenia were defined through advanced genetic techniques. Molecular diagnosis is useful for risk stratification, choice of therapy and prognosis on follow-up. This review was prepared for pediatricians as a guide focused on approach neutropenia, which tests should be performed and when should be referred to a specialist. (Turk Pediatri Ars 2015; 50: 136-44)

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Section: Innovations In Neutropeniamentioning

confidence: 99%

Approach to the patient with neutropenia in childhood

Çelkan

Koç

2015

Turk Pediatri Ars

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“…Most of the patients presented typical clinical manifestations of known PIDs, so that they were likely to be diagnosed based on a classical approach. Identifying gene mutations in the Iranian PID population resulted in 2 novel mutation discoveries, JAGN1 5 and STK4 6 deficiencies, which are the causes of a type of CVID and CID, respectively [31, 32]. …”

Section: Resultsmentioning

confidence: 99%

Gene mutations responsible for primary immunodeficiency disorders: A report from the first primary immunodeficiency biobank in Iran

Sheikhbahaei

Sherkat

Roos

et al. 2016

Allergy Asthma Clin Immunol

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BackgroundPrimary immunodeficiency (PID) is a heterogeneous group of inheritable genetic disorders with increased susceptibility to infections, autoimmunity, uncontrolled inflammation and malignancy. Timely precise diagnosis of these patients is very essential since they may not be able to live with their congenital immunity defects; otherwise, they could survive with appropriate treatment. DNA biobanks of such patients could be used for molecular and genetic testing, facilitating the detection of underlying mutations in known genes as well as the discovery of novel genes and pathways.MethodsAccording to the last update of the International Union of Immunological Societies (IUIS) classification, patients are registered in our biobank during a period of 15 years. All patients’ data were collected via questionnaire and their blood samples were taken in order to extract and protect their DNA content.ResultsOur study comprised 197 patients diagnosed with PID. Antibody deficiency in 50 patients (25.4%), phagocytic defect in 47 patients (23.8%) and combined immunodeficiency with associated/syndromic feature in 19 patients (9.6%) were the most common PID diagnoses, respectively. The most common variant of PID in our study is common variable immunodeficiency, which accounted for 20 cases (10.1%), followed by chronic mucocutaneous candidiasis in 15 patients (7.9%) and congenital neutropenia in 13 patients (7%). Mean age at onset of disease was 4 years and mean age of diagnosis was 9.6 years. The average diagnostic delay was 5.5 years, with a range of 6 months to 46 years. Parental consanguinity and history of PID in family were observed in 70.2 and 48.9% of the patients, respectively. The majority of PID patients (93.3%) were from families with low socioeconomic status.ConclusionThis prospective study was designed to establish a PID Biobank in order to have a high quality DNA reservoir of these patients, shareable for international diagnostic and therapeutic collaborations. This article emphasizes the need to raise the awareness of society and general practitioners to achieve timely diagnosis of these patients and prevent current mismanagements.

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“…Beispielsweise konnten wir zeigen, dass einer schweren systemischen Lupus-erythematodes-artigen Autoimmunerkrankung eine Defizienz der Proteinkinase-C-δ (PRKCD) zugrunde liegt und mit einer vermehrten Aktivität der Inteleukin(IL)-6-abhängigen Signalkaskade einhergeht -entsprechend könnte die IL6-Rezeptor-Blockade eine erfolgversprechende Therapie darstellen [5]. Andere Beispiele sind die Substitution von rekombinantem IL21 für die Behandlung der IL21-Defizienz [6] oder die Stimulation der Granulopoese durch Granulozyten-Makrophagen-Kolonie-stimulierenden Faktor (GM-CSF) bei einer spezifischen Subform der schweren kongenitalen Neutropenie, die durch Mutationen im JAGN1-Gen hervorgerufen wird und häufig resistent gegen die sonst übliche Therapie mit Granulozyten-Kolonie-stimulierendem Faktor (G-CSF) ist [7,8] …”

Section: Erforschung Seltener Erkrankungen Als Wegbereiter Für Personunclassified

Wiener Zentrum für seltene und nicht diagnostizierte Erkrankungen

Boztuğ

2015

Paediatr. Paedolog. Austria

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JAGN1 deficiency causes aberrant myeloid cell homeostasis and congenital neutropenia

Cited by 118 publications

References 51 publications

Approach to the patient with neutropenia in childhood

Approach to the patient with neutropenia in childhood

Gene mutations responsible for primary immunodeficiency disorders: A report from the first primary immunodeficiency biobank in Iran

Wiener Zentrum für seltene und nicht diagnostizierte Erkrankungen

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