TBX1 Is Responsible for Cardiovascular Defects in Velo-Cardio-Facial/DiGeorge Syndrome
CellPublished 1 February 2001
Sandra Merscher, Birgit Funke, Jonathan A. Epstein, Joerg Heyer, Anne Puech, Min Lü
Citations975
SJR quartileQ1
SJR score22.61
SNIP7.62
Generate an AI Snapshot to get a quick, structured summary of this paper.
Study Snapshot
ObjectiveStudy objective
MethodsResearch methodology
PopulationPopulation studied
Sample sizeSample sizes
OutcomesStudy outcomes here
ResultsStudy results comes here
LimitationsResearch study limitations comes here
A concise AI-generated summary of the paper will appear here once you click Generate AI Snapshot.
TL;DR
A major role is suggested for this gene in the molecular etiology of VCFS/DGS using a cre-loxP strategy to generate mice that are hemizygous for a 1.5-3.0 Mb deletion corresponding to that on 22q11.
Abstract
Velo-cardio-facial syndrome (VCFS)/DiGeorge syndrome (DGS) is a human disorder characterized by a number of phenotypic features including cardiovascular defects. Most VCFS/DGS patients are hemizygous for a 1.5-3.0 Mb region of 22q11. To investigate the etiology of this disorder, we used a cre-loxP strategy to generate mice that are hemizygous for a 1.5 Mb deletion corresponding to that on 22q11. These mice exhibit significant perinatal lethality and have conotruncal and parathyroid defects. The conotruncal defects can be partially rescued by a human BAC containing the TBX1 gene. Mice heterozygous for a null mutation in Tbx1 develop conotruncal defects. These results together with the expression patterns of Tbx1 suggest a major role for this gene in the molecular etiology of VCFS/DGS.
Keywords
MedicineBiochemistry, Genetics and Molecular Biology
Cambridge University Press eBooksThe Neural Crest
3,021 Citations1999Nicole Le Douarin, Chaya Kalcheim
NatureThe DNA sequence of human chromosome 21
1,476 Citations2000Masahira Hattori, Asao Fujiyama +61 more
The sequence and gene catalogue of the long arm of chromosome 21, the smallest human autosome, is reported, and structural features identified include duplications that are probably involved in chromosomal abnormalities and repeat structures in the telomeric and pericentromeric regions.
Journal of Medical GeneticsSpectrum of clinical features associated with interstitial chromosome 22q11 deletions: a European collaborative study.
1,197 Citations1997A K Ryan, Judith A. Goodship +23 more
The majority of patients were constitutionally small, with 36% of patients below the 3rd centile for either height or weight parameters, and the majority of surviving patients were developmentally normal or had only mild learning problems.
NatureThe DNA sequence of human chromosome 22
1,162 Citations1999Ian Dunham, Adrienne Hunt +215 more
The sequence of the euchromatic part of human chromosome 22 is reported, which consists of 12 contiguous segments spanning 33.4 megabases, contains at least 545 genes and 134 pseudogenes, and provides the first view of the complex chromosomal landscapes that will be found in the rest of the genome.
Nature GeneticsMutations in human cause limb and cardiac malformation in Holt-Oram syndrome
1,106 Citations1997Craig T. Basson, David R. Bachinsky +12 more
It is concluded that TBX5 is critical for limb and heart development and suggest that haploinsufficiency ofTBX5 causes Holt-Oram syndrome.
ScienceNeural Crest Cells Contribute to Normal Aorticopulmonary Septation
1,105 Citations1983Margaret L. Kirby, Thomas F. Gale +1 more
By analyzing the hearts of quail-chick chimeras, it was found that neural crest cells at the level of occipital somites 1 to 3 migrate to the region of the aorticopulmonary septum, resulting in common arterial outflow channels or transposition of the great vessels.
Nature GeneticsHolt-Oram syndrome is caused by mutations in TBX5, a member of the Brachyury (T) gene family
929 Citations1997Li Qy, Newbury-Ecob Ra +15 more
Tissue in situ hybridization studies on human embryos from days 26 to 52 of gestation reveal expression of TBXS in heart and limb, consistent with a role in human embryonic development.
Developmental DynamicsExpression of the T-box family genes,Tbx1-Tbx5, during early mouse development
655 Citations1996Deborah L. Chapman, Nancy Garvey +8 more
Examining the expression of 5 of these genes, Tbx1–Tbx5, across a wide range of embryonic stages from blastocyst through gastrulation and early organogenesis by in situ hybridization of wholemounts and tissue sections shows a good indication that the T‐box family of genes has important roles in inductive interactions in many stages of mammalian embryogenesis.
PubMedA new syndrome involving cleft palate, cardiac anomalies, typical facies, and learning disabilities: velo-cardio-facial syndrome.
598 Citations1978Robert J. Shprintzen, Rosalie Goldberg +5 more
A pattern of similarities among 12 patients is described which is felt to represent a newly recognized congenital malformation syndrome and the symptoms shown most consistently by the 12 patients were overt or submuscous clefts of the secondary palate, ventricular septal defects, typical facies, and learning disabilities.
Nature GeneticsMutations in human TBX3 alter limb, apocrine and genital development in ulnar-mammary syndrome
546 Citations1997Michael J. Bamshad, Robert C. Lin +13 more
It is demonstrated that mutations in human T8X3, a member of the T-box gene family, cause ulnar-mammary syndrome in two families and suggested that during the evolution of TBX3 and TBX5 from a common ancestral gene, each has acquired specific yet complementary roles in patterning the mammalian upper limb.
ScienceDependence of Thymus Development on Derivatives of the Neural Crest
469 Citations1984Dale E. Bockman, Margaret L. Kirby
Elimination of limited areas of the cephalic neural crest in stage 9 or 10 chick embryos markedly reduced the size of the thymus gland or resulted in its absence.
American Journal of Medical GeneticsVelo‐cardio‐facial syndrome: A review of 120 patients
432 Citations1993Rosalie Goldberg, Beth Motzkin +3 more
The full spectrum of VCFS is described, including several new manifestations, to compare the VCFS phenotype with published cases of "familial DiGeorge sequence" which are now thought to represent examples ofVCFS.
NatureCongenital heart disease in mice deficient for the DiGeorge syndrome region
426 Citations1999Elizabeth A. Lindsay, Annalisa Botta +6 more
The Df1/+ mouse model reveals the pathogenic basis of the most clinically severe aspect of DiGeorge syndrome and uncovers a new mechanism leading to aortic arch abnormalities.
The Journal of PediatricsThe spectrum of the DiGeorge syndrome
403 Citations1979Mary Ellen Conley, J. Bruce Beckwith +2 more
Most of the patients surviving the first month of life developed purulent rhinitis, maculopapular rashes, failure to thrive, and developmental delay, while the 24 autopsied cases constitute 0.7% of the 3,469 sequential postmortem studies done in the period 1950--1975 at The Children's Orthopedic Hospital and Medical Center.
Nature NeuroscienceThe septin CDCrel-1 binds syntaxin and inhibits exocytosis
377 Citations1999Crestina L. Beites, Hong Xie +2 more
Data suggest that septins may regulate vesicle dynamics through interactions with syntaxin, and this protein was associated with membrane fractions, and a significant fraction of the protein copurified and coprecipitated with synaptic vesicles.
Current BiologyZp3–cre, a transgenic mouse line for the activation or inactivation of loxP-flanked target genes specifically in the female germ line
367 Citations1997Mark Lewandoski, Karen M. Wassarman +1 more
A mouse line in which cre expression is controlled by regulatory sequences from the mouse zona pellucida 3 (Zp3) gene, which is normally expressed exclusively in the growing oocyte prior to the completion of the first meiotic division is described.
Proceedings of the National Academy of SciencesDifferent <i>TBX5</i> interactions in heart and limb defined by Holt–Oram syndrome mutations
365 Citations1999Craig T. Basson, Taosheng Huang +18 more
Structural data suggest that organ-specific gene activation by TBX5 is predicated on biophysical interactions with different target DNA sequences.
The American Journal of Human GeneticsMolecular Definition of 22q11 Deletions in 151 Velo-Cardio-Facial Syndrome Patients
363 Citations1997Christine Carlson, Howard I. Sirotkin +12 more
The extent of the deletion was defined, by genotyping 151 VCFS patients and performing haplotype analysis on 105, and it was found that 83% had a deletion and >90% of these had a similar approximately 3 Mb deletion, suggesting that sequences flanking the common breakpoints are susceptible to rearrangement.
The American Journal of CardiologyCardiovascular anomalies in digeorge syndrome and importance of neural crest as a possible pathogenetic factor
360 Citations1986Lodewyk H.S. Van Mierop, Lynn M. Kutsche
Observations support the view that DiGeorge syndrome and the associated cardiovascular anomalies are due to an abnormal developmental process involving the neural crest.
Annual Review of PhysiologyROLE OF CARDIAC NEURAL CREST CELLS IN CARDIOVASCULAR DEVELOPMENT
277 Citations1998Tony L. Creazzo, Robert E. Godt +3 more
Evidence indicates that poor viability is from impaired cardiac excitation-contraction coupling and contractile function at the myocyte level, and the continued study of experimental and genetically defined models with neural crest-associated heart defects will prove useful in identifying the common pathways by which the neural crest contributes to normal heart development.
Proceedings of the National Academy of SciencesGeneration and rescue of a murine model of platelet dysfunction: The Bernard-Soulier syndrome
269 Citations2000Jerry Ware, Susan Russell +1 more
An in vivo model is defined for analysis of the human GP Ib-IX-V receptor and its role in the processes performed exclusively by megakaryocytes and platelets, and a murine model recapitulating the hallmark characteristics of thehuman Bernard-Soulier syndrome is described.
PubMedMolecular definition of the 22q11 deletions in velo-cardio-facial syndrome.
245 Citations1995Bernice E. Morrow, Rosalie Goldberg +8 more
Haplotypes generated from this study revealed that 82% of the patients have deletions that can be defined by the STRP markers, and all patients who have a deletion share a common proximal breakpoint, while there are two distinct distal breakpoints.
American Journal of AnatomyEffect of neural crest ablation on development of the heart and arch arteries in the chick
179 Citations1987Dale E. Bookman, Mary E. Redmond +3 more
It is significant that heart morphology was altered before septation of the outflow tract normally occurs, which indicates at the least that another factor, such as altered blood flow, contributes to the abnormal development.
GenomicsIsolation and Characterization of a Gene from the DiGeorge Chromosomal Region Homologous to the MouseTbx1Gene
169 Citations1997Carla Chieffo, Nancy Garvey +6 more
The identification, cloning, and characterization of the human TBX1 gene is described, which maps to the center of the DiGeorge chromosomal region, and the mouse cDNA sequence is extended to permit comparisons between human and mouse Tbx1.
Human Molecular GeneticsDeletion of 150 kb in the Minimal Digeorge/Velocardiofacial Syndrome Critical Region in Mouse
117 Citations1999Wendy L. Kimber, P. Hsieh +10 more
Journal of Biological ChemistryStructural characterization and chromosomal location of the gene encoding human platelet glycoprotein Ib beta
81 Citations1994Mayumi Yagi, Susanne Edelhoff +2 more
The G PIb beta gene has a simple structure, similar to that of other described megakaryocyte/platelet genes, including those of the GPIb-V-IX system.
Proceedings of the National Academy of SciencesNormal cardiovascular development in mice deficient for 16 genes in 550 kb of the velocardiofacial/ DiGeorge syndrome region
68 Citations2000Anne Puech, Bruno Saint-Jore +8 more
A strategy for selecting cell lines with defined chromosomal rearrangements based on reconstitution of a dominant selection marker after Cre-mediated recombination of LoxP sites is described, which should be widely applicable to many cell lines.
Annual Review of PhysiologyMOLECULAR INSIGHTS INTO CARDIAC DEVELOPMENT
66 Citations1998Henry M. Sucov
This review summarizes the author's interpretation of current trends in the effort to understand the molecular basis of cardiac-development, with an emphasis on insights obtained from genetic models.
Pediatric ResearchTranscriptional Regulation of Cardiac Development: Implications for Congenital Heart Disease and DiGeorge Syndrome
56 Citations2000Jonathan A. Epstein, Clayton A. Buck
Preliminary results support the contention that a thorough understanding of molecular programs governing cardiac morphogenesis will provide important insights into the pathogenesis of human cardiac diseases.
Human GeneticsA human gene similar to Drosophila melanogaster peanut maps to the DiGeorge syndrome region of 22q11
34 Citations1997Judith M. McKie, Helen Sutherland +3 more
A Drosophila-related expressed sequence tag (DRES) with sequence similarity to the peanut gene has previously been localized to human chromosome 22q11.2 and it is shown that it is a novel member of the family of septin genes, which encode proteins with GTPase activity thought to interact during cytokinesis.
Journal of Medical GeneticsSpectrum of clinical features associated with interstitial chromosome 22q11 deletions.
30 Citations1998Mattia Rocco, A. Buocompagni +4 more
Journal of Pediatric Endocrinology and MetabolismThyroid Abnormalities as a Feature of DiGeorge Syndrome: A Patient Report and Review of the Literature
29 Citations1998Rosie Scuccimarri, Celia Rodd
This case suggests that thyroid gland dysgenesis may be more common than previously thought and children with the DiGeorge syndrome may be at higher risk for hypothyroidism, and patients who are considered to have this anomaly should have early newborn thyroid screening.
PubMedDiGeorge syndrome presenting as severe congenital heart disease in the newborn.
22 Citations1977J. P. Finley, George F. Collins +2 more
Necropsy data lent support to the hypothesis of a relation between the cardiovascular anomalies and defective development of structures derived from the third and fourth pharyngeal pouches.
GenomicsIsolation and Characterization of a Novel Gene Containing WD40 Repeats from the Region Deleted in Velo–cardio–facial/ DiGeorge Syndrome on Chromosome 22q11
20 Citations2001Birgit Funke, Raj K. Pandita +1 more
A novel human gene is identified and characterized within the 1.5-Mb region deleted in VCFS/DGS, trisomic in der(22) syndrome and tetrasomic in CES, which contains several WD40 repeats, but lack homology to known proteins.
Velo-cardio-facial Syndrome
20 Citations2010Kevin M. Antshel, Robert J. Shprintzen
Mechanisms of DevelopmentExpression of Cdcrel-1 (Pnutl1), a gene frequently deleted in velo-cardio-facial syndrome/DiGeorge syndrome
16 Citations2000Joanna Maldonado‐Saldivia, Birgit Funke +4 more
Based on the expression pattern as well as clinical data, Cdcrel-1 may be involved in the etiology of VCFS/DGS, and hCDCREL-1 maps to chromosome 22q11.2, a region commonly deleted in patients displaying velo-cardio-facial syndrome or DiGeorge syndrome.