Dataset Information

TCF3 haploinsufficiency defined by immune, clinical, gene-dosage, and murine studies.

ABSTRACT:

Background

TCF3 is a transcription factor contributing to early lymphocyte differentiation. Germline monoallelic dominant negative and biallelic loss-of-function (LOF) null TCF3 mutations cause a fully penetrant severe immunodeficiency. We identified 8 individuals from 7 unrelated families with monoallelic LOF TCF3 variants presenting with immunodeficiency with incomplete clinical penetrance.

Objective

We sought to define TCF3 haploinsufficiency (HI) biology and its association with immunodeficiency.

Methods

Patient clinical data and blood samples were analyzed. Flow cytometry, Western blot analysis, plasmablast differentiation, immunoglobulin secretion, and transcriptional activity studies were conducted on individuals carrying TCF3 variants. Mice with a heterozygous Tcf3 deletion were analyzed for lymphocyte development and phenotyping.

Results

Individuals carrying monoallelic LOF TCF3 variants showed B-cell defects (eg, reduced total, class-switched memory, and/or plasmablasts) and reduced serum immunoglobulin levels; most but not all presented with recurrent but nonsevere infections. These TCF3 LOF variants were either not transcribed or translated, resulting in reduced wild-type TCF3 protein expression, strongly suggesting HI pathophysiology for the disease. Targeted RNA sequencing analysis of T-cell blasts from TCF3-null, dominant negative, or HI individuals clustered away from healthy donors, implying that 2 WT copies of TCF3 are needed to sustain a tightly regulated TCF3 gene-dosage effect. Murine TCF3 HI resulted in a reduction of circulating B cells but overall normal humoral immune responses.

Conclusion

Monoallelic LOF TCF3 mutations cause a gene-dosage-dependent reduction in wild-type protein expression, B-cell defects, and a dysregulated transcriptome, resulting in immunodeficiency. Tcf3^+/- mice partially recapitulate the human phenotype, underscoring the differences between TCF3 in humans and mice.

SUBMITTER: Boast B

PROVIDER: S-EPMC10527523 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Publications

TCF3 haploinsufficiency defined by immune, clinical, gene-dosage, and murine studies.

Boast Brigette B Goel Shubham S González-Granado Luis I LI Niemela Julie J Stoddard Jennifer J Edwards Emily S J ESJ Seneviratne Sandali S Spensberger Dominik D Quesada-Espinosa Juan F JF Allende Luis M LM McDonnell John J Haseley Alexandria A Lesmana Harry H Walkiewicz Magdalena A MA Muhammad Emad E Bosco Julian J JJ Fleisher Thomas A TA Cohen Shai S Holland Steven M SM van Zelm Menno C MC Enders Anselm A Kuehn Hye Sun HS Rosenzweig Sergio D SD

The Journal of allergy and clinical immunology 20230603 3

<h4>Background</h4>TCF3 is a transcription factor contributing to early lymphocyte differentiation. Germline monoallelic dominant negative and biallelic loss-of-function (LOF) null TCF3 mutations cause a fully penetrant severe immunodeficiency. We identified 8 individuals from 7 unrelated families with monoallelic LOF TCF3 variants presenting with immunodeficiency with incomplete clinical penetrance.<h4>Objective</h4>We sought to define TCF3 haploinsufficiency (HI) biology and its association wi ...[more]

PMID: 37277074

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Project description:BACKGROUND:The inactivation of tumor suppressor genes follows Alfred Knudson's 'two-hit' model: both alleles need to be inactivated by independent mutation events to trigger tumor formation. However, in a minority of tumor suppressor genes a single hit is sufficient to initiate tumorigenesis notwithstanding the presence of the wild-type allele, a condition known as haploinsufficiency. The SMAD4 gene is an intracellular mediator of the TGF-beta and BMP signal transduction pathways and a tumor suppressor involved in pancreatic and colorectal tumorigenesis. In Smad4-mutant mouse models, haploinsufficiency characterizes the development of gastrointestinal polyps with initial retention of the wild-type allele and protein expression within the nascent tumors and in their direct microenvironment. Similarly, germline SMAD4 mutations are responsible for a subset of patients affected by juvenile polyposis syndrome, an autosomal dominant intestinal cancer syndrome. To date, the molecular and cellular consequences of SMAD4 haploinsufficiency on TGF-beta and BMP signaling and on genome-wide gene expression have not been investigated. RESULTS:Here we show that, similar to previous observations in Smad4-mutant mouse models, haploinsufficiency characterizes a substantial fraction of the juvenile polyps arising in patients with germline SMAD4 mutations. Also, mouse embryonic and intestinal cells heterozygous for a targeted Smad4 null mutation are characterized by a corresponding 50% reduction of the Smad4 protein levels. Reporter assays revealed that mouse Smad4+/- cells exert intermediate inhibitory effects on both TGF-beta and BMP signaling. Genome-wide expression profiling analysis of Smad4+/- and Smad4-/- cells pinpointed a subset of dosage-dependent transcriptional target genes encompassing, among others, members of the TGF-beta and Wnt signaling pathways. These SMAD4 dosage-dependent transcriptional changes were confirmed and validated in a subset of target genes in intestinal tissues from juvenile polyposis syndrome patients. CONCLUSION:Smad4 haploinsufficiency is sufficient to significantly inhibit both TGF-beta and BMP signal transduction and results in the differential expression of a broad subset of target genes likely to underlie tumor formation both from the mesenchymal and epithelial compartments. The results of our study, performed in normal rather than tumor cells where additional (epi-) genetic alterations may confound the analysis, are relevant for our understanding and elucidation of the initial steps underlying SMAD4-driven intestinal tumorigenesis.

Dataset Information

TCF3 haploinsufficiency defined by immune, clinical, gene-dosage, and murine studies.

Background

Objective

Methods

Results

Conclusion

Publications

TCF3 haploinsufficiency defined by immune, clinical, gene-dosage, and murine studies.

Similar Datasets

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