Vitamin B12 ameliorates the phenotype of a mouse model of DiGeorge syndrome

Lania, Gabriella; Bresciani, Alberto; Bisbocci, Monica; Francone, Alessandra; Colonna, Vincenza; Altamura, Sergio; Baldini, Antonio

doi:10.1093/hmg/ddx353

Cited by 3 publications

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“…Furthermore, for both alleles, and for both drugs, the phenotypic rescue was complete, for the markers tested. This is in contrast to the cardiovascular phenotype, for which only partial rescue was obtained (Fulcoli et al, 2016; Lania et al, 2016). Thus, the brain seems to be more sensitive than the heart to the beneficial effects of these two drugs.…”

Section: Discussionmentioning

confidence: 59%

“…Vitamin B12 (B12) was identified in a high throughput screen (HTS) to identify small molecules that enhanced Tbx1 gene expression in Tbx1 heterozygous mouse embryonic fibroblasts (Lania et al, 2016). The authors of this study reported the partial rescue of cardiovascular phenotypes in mid- and pre-term Tbx1 mutant embryos when treated with high doses of B12.…”

Section: Resultsmentioning

confidence: 99%

“…The rescue of phenotypes caused by deficiency of Tbx1 , which encodes a transcription factor, presents special challenges because of the potential number and variety of target genes. Nevertheless, research has identified a number of targeted strategies that have been successful in ameliorating the cardiovascular phenotype (Caprio and Baldini, 2014; Fulcoli et al, 2016; Lania et al, 2016; Racedo et al, 2017; Vitelli et al, 2010). However, the brain cortex phenotype has never been tested.…”

Section: Introductionmentioning

confidence: 99%

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Pharmacological rescue of the brain cortex phenotype ofTbx1mouse mutants: significance for 22q11.2 deletion syndrome

Favicchia

Flore

Lania

et al. 2021

Preprint

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Objectives: Tbx1 mutant mice are a widely used model of 22q11.2 deletion syndrome (22q11.2DS) because they manifest a broad spectrum of physical and behavioral abnormalities that is similar to that found in 22q11.2DS patients. In Tbx1 mutants, brain abnormalities include changes in cortical cytoarchitecture, hypothesized to be caused by the precocious differentiation of cortical progenitors. The objectives of this research are to identify drugs that have efficacy against the brain phenotype, and through a phenotypic rescue approach, gain insights into the pathogenetic mechanisms underlying Tbx1 haploinsufficiency. Experimental approach: Disease model: Tbx1 heterozygous and homozygous embryos. We tested the ability of two FDA-approved drugs, the LSD1 inhibitor Tranylcypromine and Vitamin B12, to rescue the Tbx1 mutant cortical phenotype. Both drugs have proven efficacy against the cardiovascular phenotype, albeit at a much reduced level compared to the rescue achieved in the brain. Methods: in situ hybridization and immunostaining of histological brain sections using a subset of molecular markers that label specific cortical regions or cell types. Appropriate quantification and statistical analysis of gene and protein expression were applied to identify cortical abnormalities and to determine the level of phenotypic rescue achieved. Results: Cortical abnormalities observed in Tbx1 mutant embryos were fully rescued by both drugs. Intriguingly, rescue was obtained with both drugs in Tbx1 homozygous mutants, indicating that they function through mechanisms that do not depend upon Tbx1 function. This was particularly surprising for Vitamin B12, which was identified through its ability to increase Tbx1 gene expression. Conclusions: To our knowledge, this is only the second example of drugs to be identified that ameliorate phenotypes caused by the mutation of a single gene from the 22q11.2 homologous region of the mouse genome. This one drug-one gene approach might be important because there is evidence that the brain phenotype in 22q11.2DS patients is multigenic in origin, unlike the physical phenotypes, which are overwhelmingly attributable to Tbx1 haploinsufficiency. Therefore, effective treatments will likely involve the use of multiple drugs that are targeted to the function of specific genes within the deleted region.

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Section: Discussionmentioning

confidence: 59%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pharmacological rescue of the brain cortex phenotype ofTbx1mouse mutants: significance for 22q11.2 deletion syndrome

Favicchia

Flore

Lania

et al. 2021

Preprint

Self Cite

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“…Although these genetic approaches are important, it is difficult to translate them to the clinical setting. A recent study using a high-throughput screening approach identified vitamin B12 as a molecule capable of enhancing Tbx1 gene expression (Lania et al 2016). Using Tbx1 lacZ/+ mice as a readout, vitamin B12 was shown to increase expression of Tbx1 in vivo and partially rescue the Tbx1 haploinsufficient phenotype.…”

Section: Murine Models Of Conotruncal and Aortic Arch Artery Defectsmentioning

confidence: 99%

In Vivo and In Vitro Genetic Models of Congenital Heart Disease

Majumdar

Yasuhara

Garg

2019

Cold Spring Harb Perspect Biol

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Congenital cardiovascular malformations represent the most common type of birth defect and encompass a spectrum of anomalies that range from mild to severe. The etiology of congenital heart disease (CHD) is becoming increasingly defined based on prior epidemiologic studies that supported the importance of genetic contributors and technological advances in human genome analysis. These have led to the discovery of a growing number of disease-contributing genetic abnormalities in individuals affected by CHD. The evergrowing population of adult CHD survivors, which are the result of reductions in mortality from CHD during childhood, and this newfound genetic knowledge have led to important questions regarding recurrence risks, the mechanisms by which these defects occur, the potential for novel approaches for prevention, and the prediction of long-term cardiovascular morbidity in adult CHD survivors. Here, we will review the current status of genetic models that accurately model human CHD as they provide an important tool to answer these questions and test novel therapeutic strategies.

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“…CC-BY-NC-ND 4.0 International license made available under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is The copyright holder for this preprint this version posted May 14, 2020. ; https://doi.org/10.1101/2020.05.12.087452 doi: bioRxiv preprint leads to the discovery of potential therapeutic measures to rescue cardiovascular defect through pharmaceutical manipulation of TBX1-involved biological pathway (11)(12)(13). Interestingly, untypical 22q11.2 deletions outside of the 1.5 Mbs critical region are also associated with CHD (14)(15)(16).…”

Section: Introductionmentioning

confidence: 99%

SORBS2is a genetic factor contributing to cardiac malformation of 4q deletion syndrome

Liang

Zhang

Wang

et al. 2020

Preprint

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24Chromosome 4q deletion is one of the most frequently detected genomic imbalance events 25 in congenital heart disease (CHD) patients. However, a portion of CHD-associated 4q deletions 26 do not include known CHD genes. Alignment of those 4q deletions defined a minimal 27 overlapping region including only one gene-SORBS2. Histological analysis of Sorbs2 -/heart 28 revealed atrial septal hypoplasia/aplasia or double atrial septum. Mechanistically, SORBS2 had 29 a dual role in maintaining sarcomeric integrity of cardiomyocytes and specifying the fate of 30 second heart field (SHF) progenitors through c-ABL/NOTCH/SHH axis. In a targeted 31 sequencing of a panel of known and candidate CHD genes on 300 CHD cases, we found that 32 rare SORBS2 variants were significantly enriched in CHD patients. Our findings indicate that 33 SORBS2 is a regulator of cardiac development and its haploinsufficiency may contribute to 34 cardiac phenotype of 4q deletion syndrome. The presence of double atrial septum in Sorbs2 -/-35 hearts reveals the first molecular etiology of this rare anomaly linked to paradoxical 36 thromboembolism. 37 38 39 Keywords: 4q deletion syndrome, Congenital heart disease, SORBS2, second heart field, 40 Notch1 41 42 3 Introduction 43Congenital heart disease (CHD) is present in ~1% newborns (1). Although CHD is the most 44 common birth defect, the underlying causes of most CHDs remain elusive. Genetic 45 heterogeneity and gene-environment interaction limit the genotype-phenotype correlation and 46 complicate interpretation of CHD genetics. Anatomic rectification through interventional and 47 surgical treatments have greatly improved survival rate of CHD patients (2). However, the same 48 medical treatment often yields different outcomes in different CHD patients, suggesting the 49 underlying genetic lesion impacts CHD prognosis. Therefore, elucidation of CHD genetic basis 50 is becoming ever more important in both reducing short-term therapeutic complications and 51 improving long-term care of CHD patients. With the advances in genetic diagnosis techniques, 52 the discovery of genetic variants is no longer a limit (3). The interpretation of the association 53 of identified genetic variants with phenotype becomes the imperative need to address the 54 genetic basis of CHD. 55CNV is a chromosomal structural aberration comprising of deletion or duplication with a 56 size larger than 1kb. Due to the abundance of low-copy repeats and retrotransposons, CNVs 57 are quite common genetic variants in human genomes. Previous studies have estimated that 58 CNVs contribute to 10-15% CHD (4, 5). The most common chromosomal deletion is 59 Del22q11.2, which is the shared genetic cause of 3 clinical syndromes-DiGeorge syndrome, 60 velocardiofacial syndrome and conotruncal anomaly face syndrome (6). The common forms of 61 Del22q11.2 are ~3 or 1.5 Mbs deletion encompassing dozens of genes (6). The successful 62 identification of the major CHD gene TBX1 has greatly advanced our understanding of the 63 pathogenesis of 22q11.2 del...

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Vitamin B12 ameliorates the phenotype of a mouse model of DiGeorge syndrome

Cited by 3 publications

References 0 publications

Pharmacological rescue of the brain cortex phenotype ofTbx1mouse mutants: significance for 22q11.2 deletion syndrome

Pharmacological rescue of the brain cortex phenotype ofTbx1mouse mutants: significance for 22q11.2 deletion syndrome

In Vivo and In Vitro Genetic Models of Congenital Heart Disease

SORBS2is a genetic factor contributing to cardiac malformation of 4q deletion syndrome

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