Homozygous transcription factor 3 gene  (TCF3)  mutation is associated with severe hypogammaglobulinemia and B-cell acute lymphoblastic leukemia

Ben-Ali, Meriem; Yang, Jing; Chan, Koon Wing; Ben‐Mustapha, Imen; Mekki, Najla; Benabdesselem, Chaouki; Mellouli, Fethi; Béjaoui, Mohamed; Yang, Wanling; Aissaouï, Lamia; Lau, Yu Lung; Barbouche, Mohamed‐Ridha

doi:10.1016/j.jaci.2017.04.037

Cited by 43 publications

(33 citation statements)

References 9 publications

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“…Similarly, we reported a novel AR mode of inheritance for the previously reported AD agammaglobulinemia caused by heterozygous dominant‐negative de novo mutation in transcription factor 3 ( TCF3 ) gene . This novel AR TCF3 deficiency is associated with severe hypogammaglobulinemia and B‐cell acute lymphoblastic leukemia . Both ALPS and TCF3 deficiency novel forms are supported by parents’ consanguinity, familial history, and segregation of clinical and immunologic features with mutation homozygous status.…”

Section: Novel Form Of Ar Alps‐fas With Normal or Residual Protein Exmentioning

confidence: 69%

“…47 This novel AR TCF3 deficiency is associated with severe hypogammaglobulinemia and B-cell acute lymphoblastic leukemia. 48 Both ALPS and TCF3 deficiency novel forms are supported by parents' consanguinity, familial history, and segregation of clinical and immunologic features with mutation homozygous status. It is well known that distribution of PIDs with more than 1 mode of transmission is often different in consanguineous populations as compared to outbred ones.…”

Section: Novel Form Of Ar Alps-fas With Normal or Residual Protein Exmentioning

confidence: 99%

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Novel insights into FAS defects underlying autoimmune lymphoproliferative syndrome revealed by studies in consanguineous patients

Ben‐Mustapha

Agrebi

Barbouche

2017

Journal of Leukocyte Biology

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Autoimmune lymphoproliferative syndrome (ALPS) is a primary immunodeficiency disease due to impaired Fas-Fas ligand apoptotic pathway. It is characterized by chronic nonmalignant, noninfectious lymphadenopathy and/or splenomegaly associated with autoimmune manifestations primarily directed against blood cells. Herein, we review the heterogeneous ALPS molecular bases and discuss recent findings revealed by the study of consanguineous patients. Indeed, this peculiar genetic background favored the identification of a novel form of AR ALPS-FAS associated with normal or residual protein expression, expanding the spectrum of ALPS types. In addition, rare mutational mechanisms underlying the splicing defects of FAS exon 6 have been identified in AR ALPS-FAS with lack of protein expression. These findings will help decipher critical regions required for the tight regulation of FAS exon 6 splicing. We also discuss the genotype-phenotype correlation and disease severity in AR ALPS-FAS. Altogether, the study of ALPS molecular bases in endogamous populations helps to better classify the disease subgroups and to unravel the Fas pathway functioning.

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Section: Novel Form Of Ar Alps‐fas With Normal or Residual Protein Exmentioning

confidence: 69%

Section: Novel Form Of Ar Alps-fas With Normal or Residual Protein Exmentioning

confidence: 99%

Novel insights into FAS defects underlying autoimmune lymphoproliferative syndrome revealed by studies in consanguineous patients

Ben‐Mustapha

Agrebi

Barbouche

2017

Journal of Leukocyte Biology

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“…All novel missense mutations were predicted to be possibly or probably damaging by Polyphen2 and/or SIFT algorithms. Furthermore, a deleterious effect was confirmed by appropriate functional testing for several gene mutations including TCF3 (22), AICDA (23), NCF2 (24), FAS (25), STAT1 (21), IL12B (26), and PGM3 (27). …”

Section: Molecular Studies and Mode Of Inheritancementioning

confidence: 95%

“…Indeed, we did recently report a patient with a homozygous nonsense mutation in TCF3 gene, who presented with severe hypogammaglobulinemia, very low number of B cells and developed B-cell acute lymphoblastic leukemia (22) (Table 2). …”

Section: Identification Of Novel Gene and Of Novel Mode Of Inheritancmentioning

confidence: 99%

Lessons from Genetic Studies of Primary Immunodeficiencies in a Highly Consanguineous Population

et al. 2017

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During the last decades, the study of primary immunodeficiencies (PIDs) has contributed tremendously to unravel novel pathways involved in a variety of immune responses. Many of these PIDs have an autosomal recessive (AR) mode of inheritance. Thus, the investigation of the molecular basis of PIDs is particularly relevant in consanguineous populations from Middle East and North Africa (MENA). Although significant efforts have been made in recent years to develop genetic testing across the MENA region, few comprehensive studies reporting molecular basis of PIDs in these settings are available. Herein, we review genetic characteristics of PIDs identified in 168 patients from an inbred Tunisian population. A spectrum of 25 genes involved was analyzed. We show that AR forms compared to X-linked or autosomal dominant forms are clearly the most frequent. Furthermore, the study of informative consanguineous families did allow the identification of a novel hyper-IgE syndrome linked to phosphoglucomutase 3 mutations. We did also report a novel form of autoimmune lymphoproliferative syndrome caused by homozygous FAS mutations with normal or residual protein expression as well as a novel AR transcription factor 3 deficiency. Finally, we identified several founder effects for specific AR mutations. This did facilitate the implementation of preventive approaches through genetic counseling in affected consanguineous families. All together, these findings highlight the specific nature of highly consanguineous populations and confirm the importance of unraveling the molecular basis of genetic diseases in this context. Besides providing a better fundamental knowledge of novel pathways, their study is improving diagnosis strategies and appropriate care.

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“…B cells lacked a functional BCR, and differentiation was blocked at the common lymphoid precursor to pro-B-cell stage. However, some developmental progression along the B lineage takes place even in the complete absence of E2A/TCF3, as evidenced by a case with a homozygous nonsense E2A/TCF3 mutation and with severe hypogammaglobulinemia combined with B-ALL that was recently described (34).…”

Section: Germline Variationmentioning

confidence: 97%

Cell Fate Decisions: The Role of Transcription Factors in Early B-cell Development and Leukemia

Fischer

Yang

Ikawa

et al. 2020

Blood Cancer Discovery

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B cells are an integral part of the adaptive immune system and regulate innate immunity. Derived from hematopoietic stem cells, B cells mature through a series of cell fate decisions. Complex transcriptional circuits form and dissipate dynamically during these lineage restrictions. Genomic aberrations of involved transcription factors underlie various B-cell disorders. Acquired somatic aberrations are associated with cancer, whereas germline variations predispose to both malignant and nonmalignant diseases. We review the opposing role of transcription factors during B-cell development in health and disease. We focus on early B-cell leukemia and discuss novel causative gene-environment cooperation and their implications for precision medicine. Childhood leukemia is frequently initiated during fetal hematopoiesis. Clinical silent preleukemic clones are detectable in cord blood of a large number of healthy newborns. These predisposing alterations cooperate with environmental factors to trigger leukemia onset. Understanding of the underlying principles is a prerequisite for the development of measures to prevent leukemia in children.

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Homozygous transcription factor 3 gene (TCF3) mutation is associated with severe hypogammaglobulinemia and B-cell acute lymphoblastic leukemia

Cited by 43 publications

References 9 publications

Novel insights into FAS defects underlying autoimmune lymphoproliferative syndrome revealed by studies in consanguineous patients

Novel insights into FAS defects underlying autoimmune lymphoproliferative syndrome revealed by studies in consanguineous patients

Lessons from Genetic Studies of Primary Immunodeficiencies in a Highly Consanguineous Population

Cell Fate Decisions: The Role of Transcription Factors in Early B-cell Development and Leukemia

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