scholarly journals Pharmacological Rescue of the Brain Cortex Phenotype of Tbx1 Mouse Mutants: Significance for 22q11.2 Deletion Syndrome

2021 ◽  
Vol 14 ◽  
Author(s):  
Ilaria Favicchia ◽  
Gemma Flore ◽  
Sara Cioffi ◽  
Gabriella Lania ◽  
Antonio Baldini ◽  
...  
Keyword(s):  
Vitamin B12 ◽  
Single Gene ◽  
22Q11.2 Deletion Syndrome ◽  
Deletion Syndrome ◽  
Homologous Region ◽  
22Q11.2 Deletion ◽  
Gene And Protein Expression ◽  
Multiple Drugs ◽  
Phenotypic Rescue ◽  
The Brain

ObjectivesTbx1 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 ApproachDisease 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.MethodsIn 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.ResultsCortical 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.ConclusionTo 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.

scholarly journals Pharmacological rescue of the brain cortex phenotype of Tbx1 mouse mutants: significance for 22q11.2 deletion syndrome

2021 ◽  
Author(s):  
Ilaria Favicchia ◽  
Gemma Flore ◽  
Sara Cioffi ◽  
Gabriella Lania ◽  
Antonio Baldini ◽  
...  
Keyword(s):  
Vitamin B12 ◽  
Single Gene ◽  
22Q11.2 Deletion Syndrome ◽  
Deletion Syndrome ◽  
Homologous Region ◽  
22Q11.2 Deletion ◽  
Gene And Protein Expression ◽  
Multiple Drugs ◽  
Phenotypic Rescue ◽  
The Brain

ABSTRACTObjectivesTbx1 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 approachDisease modelTbx1 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.Methodsin 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.ResultsCortical 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.ConclusionsTo 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.

scholarly journals The 22q11.2 Deletion Syndrome: A Gene Dosage Perspective

2006 ◽  
Vol 6 ◽  
pp. 1881-1887 ◽  
Author(s):  
Antonio Baldini
Keyword(s):  
Developmental Stages ◽  
Gene Dosage ◽  
Single Gene ◽  
22Q11.2 Deletion Syndrome ◽  
Genomic Region ◽  
Deletion Syndrome ◽  
Genomic Disorder ◽  
22Q11.2 Deletion ◽  
Developmental Context

The 22q11.2 deletion/DiGeorge syndrome is a relatively common “genomic” disorder that results from heterozygous deletion of a 3-Mbp segment of chromosome 22. Of the more than 30 genes deleted in this syndrome,TBX1is the only one that has been found to be mutated in some patients with a phenotype that is very similar to that of patients with the full deletion, suggesting thatTBX1haploinsufficiency is a major contributor to the syndrome’s phenotype. Multi- and single-gene mouse models have provided a considerable amount of information about the consequences of decreased and increased dosage of the genomic region (and in particular of theTbx1gene) on mouse embryonic development. Modified alleles ofTbx1, as well as conditional ablation strategies have been utilized to mapin vivothe tissues and developmental stages most sensitive to gene dosage. These experiments have revealed substantially different sensitivity to gene dosage in different tissues and at different times, underlying the importance of the developmental context within which gene dosage reduction occurs.

scholarly journals 22q11.2 deletion syndrome and schizophrenia

2020 ◽  
Vol 52 (11) ◽  
pp. 1181-1190
Author(s):  
Xianzheng Qin ◽  
Jiang Chen ◽  
Tian Zhou
Keyword(s):  
Mouse Chromosome ◽  
Digeorge Syndrome ◽  
22Q11.2 Deletion Syndrome ◽  
Velocardiofacial Syndrome ◽  
Deletion Syndrome ◽  
22Q11.2 Deletion ◽  
Developmental Defects ◽  
Abnormal Behaviors ◽  
The Brain ◽  
Schizophrenia Susceptibility

Abstract 22q11.2 deletion is a common microdeletion that causes an array of developmental defects including 22q11.2 deletion syndrome (22q11DS) or DiGeorge syndrome and velocardiofacial syndrome. About 30% of patients with 22q11.2 deletion develop schizophrenia. Mice with deletion of the ortholog region in mouse chromosome 16qA13 exhibit schizophrenia-like abnormal behaviors. It is suggested that the genes deleted in 22q11DS are involved in the pathogenesis of schizophrenia. Among these genes, COMT, ZDHHC8, DGCR8, and PRODH have been identified as schizophrenia susceptibility genes. And DGCR2 is also found to be associated with schizophrenia. In this review, we focused on these five genes and reviewed their functions in the brain and the potential pathophysiological mechanisms in schizophrenia, which will give us a deeper understanding of the pathology of schizophrenia.

Surgical Management of Patients With 22q11.2 Deletion Syndrome

2019 ◽  
Vol 4 (5) ◽  
pp. 857-869
Author(s):  
Oksana A. Jackson ◽  
Alison E. Kaye
Keyword(s):  
Surgical Management ◽  
Preoperative Evaluation ◽  
Preoperative Assessment ◽  
22Q11.2 Deletion Syndrome ◽  
Deletion Syndrome ◽  
22Q11.2 Deletion ◽  
Surgical Decision ◽  
Obstructive Sleep ◽  
Spine Abnormalities ◽  
Speech Assessment

Purpose The purpose of this tutorial was to describe the surgical management of palate-related abnormalities associated with 22q11.2 deletion syndrome. Craniofacial differences in 22q11.2 deletion syndrome may include overt or occult clefting of the palate and/or lip along with oropharyngeal variances that may lead to velopharyngeal dysfunction. This chapter will describe these circumstances, including incidence, diagnosis, and indications for surgical intervention. Speech assessment and imaging of the velopharyngeal system will be discussed as it relates to preoperative evaluation and surgical decision making. Important for patients with 22q11.2 deletion syndrome is appropriate preoperative screening to assess for internal carotid artery positioning, cervical spine abnormalities, and obstructive sleep apnea. Timing of surgery as well as different techniques, common complications, and outcomes will also be discussed. Conclusion Management of velopharyngeal dysfunction in patients with 22q11.2 deletion syndrome is challenging and requires thoughtful preoperative assessment and planning as well as a careful surgical technique.

Psychosocial Risks and Management for Children and Adolescents With 22q11.2 Deletion Syndrome

2019 ◽  
Vol 4 (4) ◽  
pp. 633-640 ◽  
Author(s):  
Canice E. Crerand ◽  
Ari N. Rabkin
Keyword(s):  
Cognitive Abilities ◽  
Psychotic Disorders ◽  
Developmental Stages ◽  
Early Adulthood ◽  
22Q11.2 Deletion Syndrome ◽  
Deletion Syndrome ◽  
22Q11.2 Deletion ◽  
Psychosocial Risks ◽  
Empirically Supported ◽  
Specific Education

Purpose This article reviews the psychosocial risks associated with 22q11.2 deletion syndrome, a relatively common genetic condition associated with a range of physical and psychiatric problems. Risks associated with developmental stages from infancy through adolescence and early adulthood are described, including developmental, learning, and intellectual disabilities as well as psychiatric disorders including anxiety, mood, and psychotic disorders. Other risks related to coping with health problems and related treatments are also detailed for both affected individuals and their families. Conclusion The article ends with strategies for addressing psychosocial risks including provision of condition-specific education, enhancement of social support, routine assessment of cognitive abilities, regular mental health screening, and referrals for empirically supported psychiatric and psychological treatments.

Conotruncal heart defects and aortic arch anomalies in fetuses with 22q11.2 deletion syndrome

2020 ◽  
Author(s):  
I.V. Novikova, O.M. Khurs, T.V. Demidovich et all
Keyword(s):  
Aortic Arch ◽  
Heart Defects ◽  
22Q11.2 Deletion Syndrome ◽  
Ventricular Outflow Tract ◽  
Double Outlet Right Ventricle ◽  
Interrupted Aortic Arch ◽  
Left Ventricular ◽  
Deletion Syndrome ◽  
22Q11.2 Deletion ◽  
Aortic Arch Anomalies

16 second trimester fetuses with 22q11.2 deletion syndrome have been examined at anatomic-pathological investigation. Main cardiovascular diseases were ascending aorta hypoplasia with aortic valve stenosis (n = 6; 37.5%), truncus arteriosus (n = 5; 31.25%), tetralogy of Fallot (n = 3; 18.75%) and double-outlet right ventricle (n = 1; 6.25%). Ventricular septal defect was present in 16 cases. Associated aortic arch anomalies included interrupted aortic arch (n = 9; 56.25%), right aortic arch (n = 6; 37.5%), retroesophageal ring (n = 1; 6.25%) and aberrant right subclavian arteria (n = 5; 31.25%). 5 fetuses had left ventricular outflow tract obstructive lesions with interrupted aortic arch of type B combined with aberrant right subclavian arteria.

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