scholarly journals Tbx1 interacts genetically with Vegfr3 to regulate cardiac lymphangiogenesis in mice

2019 ◽  
Author(s):  
Stefania Martucciello ◽  
Maria Giuseppina Turturo ◽  
Sara Cioffi ◽  
Li Chen ◽  
Antonio Baldini ◽  
...  
Keyword(s):  
Lymphatic Vessel ◽  
Genetic Interaction ◽  
Gene Dosage ◽  
Major Gene ◽  
Lymphatic Vessels ◽  
22Q11.2 Deletion Syndrome ◽  
Differential Sensitivity ◽  
Deletion Syndrome ◽  
Loss Of Function ◽  
Compound Heterozygotes

ABSTRACTThe transcription factor TBX1 is the major gene implicated in 22q11.2 deletion syndrome. The complex clinical phenotype includes vascular anomalies and a recent report presented new cases of primary lymphedema in 22q11.2DS patients. We have previously shown that Tbx1 activates Vegfr3 gene expression in lymphatic endothelial cells and that this activation is critical for lymphatic vessel development in prenatal mice and for their survival post-natally. Using loss-of-function genetics and transgenesis, we show a strong genetic interaction between Tbx1 and Vegfr3 in cardiac lymphangiogenesis that causes cardiac lymphatic vessel anomalies in compound heterozygotes. Intriguingly, different aspects of the cardiac lymphatic phenotype were regulated independently by the two genes. Tbx1Cre-activated Vegfr3 transgene expression was able to rescue the morphological abnormalities in the cardiac lymphatic vessels of compound heterozygotes, but it did not rescue the severe cardiac lymphatic vessel hypoplasia observed in Tbx1 homozygotes. Moreover, our study revealed a differential sensitivity between the ventral and dorsal cardiac lymphatic networks to the effects of altered Tbx1 and Vegfr3 gene dosage. Overall, our study demonstrates that a fine dosage balance between Tbx1 and Vegfr3 is required to regulate the number and morphology of cardiac lymphatic vessels.

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 Loss of function mutation of mouse Snap29 on a mixed genetic background phenocopy abnormalities found in CEDNIK and 22q11.2 Deletion Syndrome patients

2019 ◽  
Author(s):  
Vafa Keser ◽  
Jean-François Boisclair Lachance ◽  
Sabrina Shameen Alam ◽  
Youngshin Lim ◽  
Eleonora Scarlata ◽  
...  
Keyword(s):  
Protein Trafficking ◽  
Genetic Background ◽  
22Q11.2 Deletion Syndrome ◽  
Deletion Syndrome ◽  
Skin Defect ◽  
Loss Of Function ◽  
22Q11.2 Deletion ◽  
Developmental Abnormalities ◽  
Mixed Genetic Background ◽  
Skin Abnormalities

AbstractSynaptosomal-associated protein 29 (SNAP29) is a member of the SNARE family of proteins involved in maintenance of various intracellular protein trafficking pathways. SNAP29 maps to the 22q11.2 region and is deleted in 90% of patients with 22q11.2 deletion syndrome (22q11.2DS). However, the contribution of hemizygosity of SNAP29 to developmental abnormalities in 22q11.2DS remains to be determined. Mutations in SNAP29 are responsible for the developmental syndrome called CEDNIK (cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma). On an inbred C57Bl/6J genetic background, only the ichthyotic skin defect associated with CEDNIK was reported. In this study, we show that loss of function mutation of Snap29 on a mixed genetic background not only models skin abnormalities found in CEDNIK, but also phenocopy ophthalmological, neurological, and motor defects found in these patients and a subset of 22q11.2DS patients. Thus, our findings indicate that mouse models of human syndromes should be analyzed on a mixed genetic background. Our work also reveals an unanticipated requirement for Snap29 in male fertility, and support contribution of hemizygosity for SNAP29 to the phenotypic spectrum of abnormalities found in 22q11.2DS patients.

scholarly journals Tbx1 regulates Vegfr3 and is required for lymphatic vessel development

2010 ◽  
Vol 189 (3) ◽  
pp. 417-424 ◽  
Author(s):  
Li Chen ◽  
Annalisa Mupo ◽  
Tuong Huynh ◽  
Sara Cioffi ◽  
Matthew Woods ◽  
...  
Keyword(s):  
Lymphatic Vessel ◽  
Perinatal Death ◽  
Major Gene ◽  
Critical Role ◽  
Lymphatic Vessels ◽  
Enhancer Element ◽  
Conditional Deletion ◽  
Tumor Lymphangiogenesis ◽  
Vessel Network ◽  
Vessel Development

Lymphatic dysfunction causes several human diseases, and tumor lymphangiogenesis is implicated in cancer spreading. TBX1 is the major gene for DiGeorge syndrome, which is associated with multiple congenital anomalies. Mutation of Tbx1 in mice recapitulates the human disease phenotype. In this study, we use molecular, cellular, and genetic approaches to show, unexpectedly, that Tbx1 plays a critical role in lymphatic vessel development and regulates the expression of Vegfr3, a gene that is essential for lymphangiogenesis. Tbx1 activates Vegfr3 transcription in endothelial cells (ECs) by binding to an enhancer element in the Vegfr3 gene. Conditional deletion of Tbx1 in ECs causes widespread lymphangiogenesis defects in mouse embryos and perinatal death. Using the mesentery as a model tissue, we show that Tbx1 is not required for lymphatic EC differentiation; rather, it is required for the growth and maintenance of lymphatic vessels. Our findings reveal a novel pathway for the development of the lymphatic vessel network.

scholarly journals Snap29 mutant mice recapitulate neurological and ophthalmological abnormalities associated with 22q11 and CEDNIK syndrome

2019 ◽  
Vol 2 (1) ◽  
Author(s):  
Vafa Keser ◽  
Jean-François Boisclair Lachance ◽  
Sabrina Shameen Alam ◽  
Youngshin Lim ◽  
Eleonora Scarlata ◽  
...  
Keyword(s):  
Protein Trafficking ◽  
Male Fertility ◽  
Genetic Background ◽  
22Q11.2 Deletion Syndrome ◽  
Deletion Syndrome ◽  
Loss Of Function ◽  
Intracellular Protein ◽  
22Q11.2 Deletion ◽  
Phenotypic Spectrum ◽  
Skin Abnormalities

Abstract Synaptosomal-associated protein 29 (SNAP29) encodes a member of the SNARE family of proteins implicated in numerous intracellular protein trafficking pathways. SNAP29 maps to the 22q11.2 region and is deleted in 90% of patients with 22q11.2 deletion syndrome (22q11.2DS). Moreover, bi-allelic SNAP29 mutations in patients are responsible for CEDNIK (cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma) syndrome. A mouse model that recapitulates abnormalities found in these syndromes is essential for uncovering the cellular basis of these disorders. In this study, we report that mice with a loss of function mutation of Snap29 on a mixed CD1;FvB genetic background recapitulate skin abnormalities associated with CEDNIK, and also phenocopy neurological and ophthalmological abnormalities found in CEDNIK and a subset of 22q11.2DS patients. Our work also reveals an unanticipated requirement for Snap29 in male fertility and supports contribution of hemizygosity for SNAP29 to the phenotypic spectrum of abnormalities found in 22q11.2DS patients.

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.

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