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Manish Butte

DDIT4 gene expression is switched on by a new HDAC4 function in ataxia telangiectasia.

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DDIT4 gene expression is switched on by a new HDAC4 function in ataxia telangiectasia.

FASEB J. 2020 01;34(1):1802-1818

Authors: Ricci A, Galluzzi L, Magnani M, Menotta M

Abstract
Ataxia telangiectasia (AT) is a rare, severe, and ineluctably progressive multisystemic neurodegenerative disease. Histone deacetylase 4 (HDAC4) nuclear accumulation has been related to neurodegeneration in AT. Since treatment with glucocorticoid analogues has been shown to improve the neurological symptoms that characterize this syndrome, the effects of dexamethasone on HDAC4 were investigated. In this paper, we describe a novel nonepigenetic function of HDAC4 induced by dexamethasone, through which it can directly modulate HIF-1a activity and promote the upregulation of the DDIT4 gene and protein expression. This new HDAC4 transcription regulation mechanism leads to a positive effect on autophagic flux, an AT-compromised biological pathway. This signaling was specifically induced by dexamethasone only in AT cell lines and can contribute in explaining the positive effects of dexamethasone observed in AT-treated patients.

PMID: 31914654 [PubMed – indexed for MEDLINE]

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Chromosome instability syndromes.

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Chromosome instability syndromes.

Nat Rev Dis Primers. 2019 09 19;5(1):64

Authors: Taylor AMR, Rothblum-Oviatt C, Ellis NA, Hickson ID, Meyer S, Crawford TO, Smogorzewska A, Pietrucha B, Weemaes C, Stewart GS

Abstract
Fanconi anaemia (FA), ataxia telangiectasia (A-T), Nijmegen breakage syndrome (NBS) and Bloom syndrome (BS) are clinically distinct, chromosome instability (or breakage) disorders. Each disorder has its own pattern of chromosomal damage, with cells from these patients being hypersensitive to particular genotoxic drugs, indicating that the underlying defect in each case is likely to be different. In addition, each syndrome shows a predisposition to cancer. Study of the molecular and genetic basis of these disorders has revealed mechanisms of recognition and repair of DNA double-strand breaks, DNA interstrand crosslinks and DNA damage during DNA replication. Specialist clinics for each disorder have provided the concentration of expertise needed to tackle their characteristic clinical problems and improve outcomes. Although some treatments of the consequences of a disorder may be possible, for example, haematopoietic stem cell transplantation in FA and NBS, future early intervention to prevent complications of disease will depend on a greater understanding of the roles of the affected DNA repair pathways in development. An important realization has been the predisposition to cancer in carriers of some of these gene mutations.

PMID: 31537806 [PubMed – indexed for MEDLINE]

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Clinical Features and HSCT Outcome for SCID in Turkey.

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Clinical Features and HSCT Outcome for SCID in Turkey.

J Clin Immunol. 2019 04;39(3):316-323

Authors: Ikinciogullari A, Cagdas D, Dogu F, Tugrul T, Karasu G, Haskologlu S, Aksoylar S, Uygun V, Kupesiz A, Yildiran A, Gursel O, Ates C, Elhan A, Kansoy S, Yesilipek A, Tezcan I, Turkish Pediatric Bone Marrow Transplantation Sub Group (TPBMT-SG)

Abstract
Severe combined immunodeficiency (SCID) is the most serious PID, characterized by T cell lymphopenia and lack of antigen-specific T cell and B cell immune responses, inevitably leading to death within the first year of life if hematopoietic stem cell transplantation (HSCT) is not performed.
PURPOSE AND METHODS: Since SCID is a common type of PID with an estimated incidence of 1/10.000 in Turkey, a retrospective analysis of HSCT characteristics, survival, immune recovery, and the major clinical features of SCID prior to HSCT is the aim of this multi-transplant center-based analysis.
RESULTS: A total of 234 SCID patients transplanted between the years 1994 and 2014 were included in the study. Median age at diagnosis was 5 months, at transplantation, 7 months, B- phenotype and RAGs were the most common defects among others. Immune phenotype did not seem to have an effect on survival rate (p > 0.05), Immunoglobulin (Ig) requirement following HSCT did not differ between B+ and B- phenotypes (p > 0.05). Overall survival rate was 65.7% over a period of 20 years. It increased from 54% (1994-2004) to 69% (p = 0.052) during the last 10 years (2005-2014). Ten-year survival after HSCT has improved over time although the difference was not significant. Infection at the time of transplantation (p = 0.006), mismatched related donor (MMRD) (haploidentical parents), and matched unrelated donor (MUD) donor transplants p < 0.001 were the most important factors, significantly affecting the outcome.
CONCLUSIONS: This is the first multicenter study with the largest data obtained from transplanted SCID patients in Turkey. Early diagnosis with newborn screening (NBS) together with emerging referrals, treatment by transplantation centers, and specialized teams are mandatory in countries with high parental consanguinity such as Turkey.

PMID: 30924026 [PubMed – indexed for MEDLINE]

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Report of a Chinese Cohort with Leukocyte Adhesion Deficiency-I and Four Novel Mutations.

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Report of a Chinese Cohort with Leukocyte Adhesion Deficiency-I and Four Novel Mutations.

J Clin Immunol. 2019 04;39(3):309-315

Authors: Sun B, Chen Q, Dong X, Liu D, Hou J, Wang W, Ying W, Hui X, Zhou Q, Yao H, Sun J, Wang X

Abstract
PURPOSE: We aimed to report the characteristics of leukocyte adhesion deficiency-I (LAD-I) and four novel mutations in the ITGB2 gene in a Chinese cohort.
METHODS: Seven patients with LAD-I were reported in our study. Clinical manifestations and immunological phenotypes were reviewed. The expression of CD18 was detected by flow cytometry. Next-generation sequencing (NGS) and Sanger sequencing were performed to identify gene mutations.
RESULTS: The mean onset age of all the patients was 1.3 months. Recurrent bacterial infections of the skin and lungs were the most common symptoms. Most patients (6/7) had delayed cord separation. The number of white blood cells (WBC) was increased significantly, except that two patients had a mild increase in the number of WBC during infection-free periods. The expression of CD18 was very low in all patients. Homozygous or compound heterozygous mutations in the ITGB2 gene were identified in each patient. Four mutations were novel, including c.1794dupC (p.N599Qfs*93), c.1788C>A (p.C596X), c.841-849del9, and c.741+1delG. Two patients had large deletions of the ITGB2 gene. Five patients were cured by hematopoietic stem cell transplantation (HSCT).
CONCLUSIONS: This study reported the clinical and molecular characteristics of a Chinese patient cohort. It is helpful in understanding the current status of the disease in China.

PMID: 30919141 [PubMed – indexed for MEDLINE]

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Human DOCK2 Deficiency: Report of a Novel Mutation and Evidence for Neutrophil Dysfunction.

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Human DOCK2 Deficiency: Report of a Novel Mutation and Evidence for Neutrophil Dysfunction.

J Clin Immunol. 2019 04;39(3):298-308

Authors: Moens L, Gouwy M, Bosch B, Pastukhov O, Nieto-Patlàn A, Siler U, Bucciol G, Mekahli D, Vermeulen F, Desmet L, Maebe S, Flipts H, Corveleyn A, Moshous D, Philippet P, Tangye SG, Boisson B, Casanova JL, Florkin B, Struyf S, Reichenbach J, Bustamante J, Notarangelo LD, Meyts I

Abstract
DOCK2 is a guanine-nucleotide-exchange factor for Rac proteins. Activated Rac serves various cellular functions including the reorganization of the actin cytoskeleton in lymphocytes and neutrophils and production of reactive oxygen species in neutrophils. Since 2015, six unrelated patients with combined immunodeficiency and early-onset severe viral infections caused by bi-allelic loss-of-function mutations in DOCK2 have been described. Until now, the function of phagocytes, specifically neutrophils, has not been assessed in human DOCK2 deficiency. Here, we describe a new kindred with four affected siblings harboring a homozygous splice-site mutation (c.2704-2 A > C) in DOCK2. The mutation results in alternative splicing and a complete loss of DOCK2 protein expression. The patients presented with leaky severe combined immunodeficiency or Omenn syndrome. The novel mutation affects EBV-B cell migration and results in NK cell dysfunction similar to previous observations. Moreover, both cytoskeletal rearrangement and reactive oxygen species production are partially impaired in DOCK2-deficient neutrophils.

PMID: 30838481 [PubMed – indexed for MEDLINE]

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Three patients with glucose-6 phosphatase catalytic subunit 3 deficiency.

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Three patients with glucose-6 phosphatase catalytic subunit 3 deficiency.

J Pediatr Endocrinol Metab. 2020 Jul 05;:

Authors: Cetinkaya PG, Cagdas D, Arikoglu T, Gumruk F, Tezcan I

Abstract
Objectives Severe congenital neutropenia (SCN) is a primary immunodeficiency (PID) characterized by persistent severe neutropenia, recurrent infections, and oral aphthous lesions. Severe congenital neutropenia is caused by various genetic defects such as ELANE, GFI, HAX-1, JAGN1, SRP54, and glucose-6 phosphatase catalytic subunit 3 (G6PC3) deficiency. Clinical features of the patients with G6PC3 deficiency vary from neutropenia to several systemic features in addition to developmental delay. Case presentation In this report, we presented three unrelated patients diagnosed with G6PC3 deficiency. All these patients had short stature, prominent and superficial vascular tissue, cardiac abnormalities (Atrial septal defect (secondary), mitral valve prolapse with mitral insufficiency, pulmonary hypertension) and lymphopenia. Patient 1 (P1) and 2 (P2) had urogenital abnormalities, P2 and P3 had thrombocytopenia. Conclusions We have shown that lymphopenia and CD4 lymphopenia do not rarely accompany to G6PC3 deficiency. Characteristic facial appearance, systemic manifestions, neutropenia could be the clues for the diagnosis of G6PC3 deficiency.

PMID: 32623377 [PubMed – as supplied by publisher]

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The recent advances in non-homologous end-joining through the lens of lymphocyte development.

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The recent advances in non-homologous end-joining through the lens of lymphocyte development.

DNA Repair (Amst). 2020 Jun 25;94:102874

Authors: Wang XS, Lee BJ, Zha S

Abstract
Lymphocyte development requires ordered assembly and subsequent modifications of the antigen receptor genes through V(D)J recombination and Immunoglobulin class switch recombination (CSR), respectively. While the programmed DNA cleavage events are initiated by lymphocyte-specific factors, the resulting DNA double-strand break (DSB) intermediates activate the ATM kinase-mediated DNA damage response (DDR) and rely on the ubiquitously expressed classical non-homologous end-joining (cNHEJ) pathway including the DNA-dependent protein kinase (DNA-PK), and, in the case of CSR, also the alternative end-joining (Alt-EJ) pathway, for repair. Correspondingly, patients and animal models with cNHEJ or DDR defects develop distinct types of immunodeficiency reflecting their specific DNA repair deficiency. The unique end-structure, sequence context, and cell cycle regulation of V(D)J recombination and CSR also provide a valuable platform to study the mechanisms of, and the interplay between, cNHEJ and DDR. Here, we compare and contrast the genetic consequences of DNA repair defects in V(D)J recombination and CSR with a focus on the newly discovered cNHEJ factors and the kinase-dependent structural roles of ATM and DNA-PK in animal models. Throughout, we try to highlight the pending questions and emerging differences that will extend our understanding of cNHEJ and DDR in the context of primary immunodeficiency and lymphoid malignancies.

PMID: 32623318 [PubMed – as supplied by publisher]

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Generation and characterization of four Chediak-Higashi Syndrome (CHS) induced pluripotent stem cell (iPSC) lines.

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Generation and characterization of four Chediak-Higashi Syndrome (CHS) induced pluripotent stem cell (iPSC) lines.

Stem Cell Res. 2020 Jun 22;47:101883

Authors: Serra-Vinardell J, Sandler MB, Pak E, Zheng W, Dutra A, Introne W, Gahl WA, Malicdan MC

Abstract
Chediak-Higashi Syndrome (CHS) is a lysosome-related organelle (LRO) disorder caused by biallelic mutations in the lysosomal trafficking regulator gene, LYST. The clinical features of CHS include oculocutaneous albinism, primary immunodeficiency, bleeding diathesis, risk for development of hemophagocyticlymphohistiocytosis,and progressive neurological problems. The pathophysiological mechanisms underlying this disease are unknown, so developing therapeutic options remains challenging. In this study,four induced pluripotent stem (iPSC) lines from unrelated CHS patients have been generated and successfully characterized for exploring the role of LYST in health and disease in diversecell types.

PMID: 32619719 [PubMed – as supplied by publisher]

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