Homozygous c.130–131 ins A (pW44X) mutation in the HAX1 gene as the most common cause of congenital neutropenia in Turkey: Report from the Turkish Severe Congenital Neutropenia Registry

Karapınar, Deniz Yılmaz; Patıroğlu, Türkan; Metìn, Ayşe; Çalışkan, Ümran; Çelkan, Tiraje; Yılmaz, Barış; Karakaş, Zeynep; Karapınar, Tuba Hilkay; Akıncı, Burcu; Özkınay, Ferda; Önay, Hüseyin; Yeşilipek, M. Akif; Akar, Himmet Haluk; Tüysüz, Gülen; Tokgöz, Hüseyin; Özdemir, Gül Nihal; Kıykım, Ayça; Karaman, Serap; Kılınç, Yurdanur; Oymak, Yeşim; Küpesiz, Alphan; Olcay, Lale; Yıldırım, Zühal; Aydoğan, Gönül; Gökçe, Müge; İleri, Talia; Aral, Yusuf Ziya; Bay, Ali; Atabay, Berna; Kaya, Zühre; Söker, Murat; Karadaş, Nihal; Özbek, Uğur; Selçuk, Bilge Özsait; Özdemir, Hamiyet Hekimci; Uygun, Vedat; Karasu, Gülsün; Yılmaz, Şebnem

doi:10.1002/pbc.27923

Cited by 21 publications

(25 citation statements)

References 28 publications

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“…The medical assessment and SCN diagnosis of the patients was performed as described previously. [ 12 ] The control group consisted of systemically healthy individuals attending the clinic of the Department of Paediatric Dentistry.…”

Section: Methodsmentioning

confidence: 99%

Dysbiosis of the Oral Ecosystem in Severe Congenital Neutropenia Patients

Zaura

Brandt

Buijs

et al. 2020

Proteomics Clinical Apps

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Purpose: To decipher the underlying immunological mechanisms in predisposition to oral microbial dysbiosis in severe congenital neutropenia (SCN) patients. Experimental Design: Ten SCN patients (5-23 years old) and 12 healthy controls (5-22 years old) are periodontally examined and provided saliva, subgingival plaque, and gingival crevicular fluid (GCF) samples. The SCN patients received oral hygiene therapy and are re-evaluated after 6 months. Antimicrobial peptides HPN1-3 and LL-37 are assessed in saliva by ELISA. Concentration of 30 cytokines is measured in saliva and GCF by human 30-plex panel, while bacterial profiles of saliva and subgingival plaque are assessed using 16S rDNA amplicon sequencing. Results: There is no significant difference in salivary HPN1-3 and LL-37 concentration between the SCN patients and controls. At baseline, clinical, immunological, and microbiological parameters of the patients are indicative of oral ecological dysbiosis. The SCN patients have significantly higher bleeding on probing (BOP)%, GCF volume, and cytokine levels, high bacterial load with low bacterial diversity in saliva. The associations between the microbiome and immunological parameters in the SCN patients differ from those in the healthy individuals. Conclusions and Clinical Relevance: SCN patients have a dysregulated immune response toward commensal oral microbiota, which could be responsible for the observed clinical and microbiological signs of dysbiosis.

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Section: Methodsmentioning

confidence: 99%

Dysbiosis of the Oral Ecosystem in Severe Congenital Neutropenia Patients

Zaura

Brandt

Buijs

et al. 2020

Proteomics Clinical Apps

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“…Digenic or multigenic mutations have been also reported in SCN patients [12]. Some mutations are linked to the geographic origin [10,[13][14][15]. Autosomal recessive (AR) HAX1 mutations account for about 15% of SCN patients, mostly from consanguineous Kurdish patients from the Middle East.…”

Section: Primary Genetic Defects Of Severe Congenital Neutropeniamentioning

confidence: 99%

“…Several genetic defects have been identified as being responsible for SCN and there is currently no clear genotype-phenotype correlation for this syndrome. Patients with ELANE, germline CSF3R mutations and WAS /X-linked severe congenital neutropenia usually present without extrahaematopoietic manifestations [10,13,14].…”

Section: Primary Genetic Defects Of Severe Congenital Neutropeniamentioning

confidence: 99%

“…HAX1 mutations affecting both isoforms (mainly p.Q190X and p.R86X) cause SCN frequently accompanied by neurological involvement (mental retardation, developmental delay, and seizures). Mutations affecting only one isoform (mainly p.W44X in Turkish patients) lead to SCN without neurological symptoms [14].…”

Section: Primary Genetic Defects Of Severe Congenital Neutropeniamentioning

confidence: 99%

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Neutropenia in Primary Immunodeficiency Diseases

Karaca¹

2021

Innate Immunity in Health and Disease

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Phagocytes including neutrophil granulocytes and macrophages are important cells of the innate immune system whose primary function is to ingest and destroy microorganisms. Neutrophils help their host fight infections by phagocytosis, degranulation, and neutrophil extracellular traps. Neutrophils are the most common type of circulating white blood cells and the principal cell type in acute inflammatory reactions. A total absence of neutrophils or a significant decrease in their number leads to severe immunodeficiency that renders patients vulnerable to recurrent infections by Staphylococcus aureus and Gram-negative bacteria being the most life-threatening. Neutropenia may be classified as mild, moderate or severe in terms of numbers in the peripheral blood, and intermittent, cyclic, or chronic in terms of duration. Besides well-known classic severe congenital neutropenia, chronic neutropenia appears to be associated with an increasing number of primary immunodeficiency diseases (PIDs), including those of myeloid and lymphoid lineage. A comprehensive overview of the diverse clinical presenting symptoms, classification, aetiological and genetic etiologies of chronic isolated and syndromic neutropenia is aimed to be reviewed.

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“…Mutations in HAX1 gene have been described in 36% of patients recorded in the Turkish Severe Congenital Neutropenia Registry. In particular, homozygous c.131G>A (p.W44X) nonsense mutation is the most common cause of congenital neutropenia in those populations [146]. Conversely, p.R86X and p.Q190X nonsense mutations are frequently detected in HAX1-mutated patients originating from Japan and Sweden [90,145].…”

Section: Severe Congenital Neutropeniamentioning

confidence: 99%

Nonsense Suppression Therapy: New Hypothesis for the Treatment of Inherited Bone Marrow Failure Syndromes

Bezzerri

Api

Allegri

et al. 2020

IJMS

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Inherited bone marrow failure syndromes (IBMFS) are a group of cancer-prone genetic diseases characterized by hypocellular bone marrow with impairment in one or more hematopoietic lineages. The pathogenesis of IBMFS involves mutations in several genes which encode for proteins involved in DNA repair, telomere biology and ribosome biogenesis. The classical IBMFS include Shwachman–Diamond syndrome (SDS), Diamond–Blackfan anemia (DBA), Fanconi anemia (FA), dyskeratosis congenita (DC), and severe congenital neutropenia (SCN). IBMFS are associated with high risk of myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and solid tumors. Unfortunately, no specific pharmacological therapies have been highly effective for IBMFS. Hematopoietic stem cell transplantation provides a cure for aplastic or myeloid neoplastic complications. However, it does not affect the risk of solid tumors. Since approximately 28% of FA, 24% of SCN, 21% of DBA, 20% of SDS, and 17% of DC patients harbor nonsense mutations in the respective IBMFS-related genes, we discuss the use of the nonsense suppression therapy in these diseases. We recently described the beneficial effect of ataluren, a nonsense suppressor drug, in SDS bone marrow hematopoietic cells ex vivo. A similar approach could be therefore designed for treating other IBMFS. In this review we explain in detail the new generation of nonsense suppressor molecules and their mechanistic roles. Furthermore, we will discuss strengths and limitations of these molecules which are emerging from preclinical and clinical studies. Finally we discuss the state-of-the-art of preclinical and clinical therapeutic studies carried out for IBMFS.

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Homozygous c.130–131 ins A (pW44X) mutation in the HAX1 gene as the most common cause of congenital neutropenia in Turkey: Report from the Turkish Severe Congenital Neutropenia Registry

Cited by 21 publications

References 28 publications

Dysbiosis of the Oral Ecosystem in Severe Congenital Neutropenia Patients

Dysbiosis of the Oral Ecosystem in Severe Congenital Neutropenia Patients

Neutropenia in Primary Immunodeficiency Diseases

Nonsense Suppression Therapy: New Hypothesis for the Treatment of Inherited Bone Marrow Failure Syndromes

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