1 Closing in on DiGeorge: Human Syndromes and Mouse Models The DiGeorge Syndrome (DGS) • Cardiac outflow tract & septal defects • Thymus and parathryoid hypoplasia • Laryngeotrachial anomalies • Craniofacial anomalies/facial dysmorphogenesis • Cleft palate • Micrognathia • Low-set, abnormal ears • Mental retardation The DiGeorge/Velocardiofacial Syndrome (DGS/VCFS) • Chr22 deletions • Overlapping clinical features with Velocardiofacial syndrome, conotruncal face syndrome • CATCH 22: Ca rdiac, T -cell deficit, C lefting, H ypocalcemia, Chromosome 22 (it lived up to its namesake!) Etiology of DGS • Variable size deletions 1.5-3MB • No common region of overlap • Contiguous gene syndrome? • Single gene haploinsufficiency? • Pharyngeal arch and pouch developmental defects • Neural crest defects Developmental Genetic Regions of Conserved Synteny Human Chromosome 22 Mouse Chromosome 16 Mouse Chromosome Synteny 6 16 10 5 11 10 8 15 22q11 22q12 22q13 Mouse Chromosome 16 DGS syntenic region genes Deletion models Candidate gene approach Znf74 Dgcr3 Idd Tsk2 Tsk1 Es2 Gscl Ctp Dgcr6 Prodh Ranbp1 Htf9c T10 Arvcf Comt TrxR2 Wdvcf Tbx1 Gp1b Cdcrel1 Tmvcf Cdc45f2 Ufd1l Nivcf Hira + + + + - - - Crkl Es2 Gscl Tbx1 Gp1b Comt Ufd1l Hira +=cardiovascular defect
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Closing in on DiGeorge: Human The DiGeorge Syndrome (DGS) … · 2007-02-02 · The DiGeorge/Velocardiofacial Syndrome (DGS/VCFS) •Chr22 deletions •Overlapping clinical features
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Closing in on DiGeorge: HumanSyndromes and Mouse Models
• 17 genes in mouse and human• Conserved DNA binding domain - the T-domain• Bind sequence-specific DNA as dimers• Affect transcription of target genes• Conserved developmental functions• Tbx1 maps to DGS region
T-domain dimer bound to DNAMuller & Herrmann (1997) Nature 389:884
sublingual and submaxillary salivary glands missing or reduced
Is TBX1 the only gene involvedin DiGeorge syndrome?
• Mouse haploinsufficiency does not recapitulate DGS• Not all DGS deletions include TBX1• Most non-deletion DGS patients do not have TBX1
mutations• However, several non-deletion pedigrees do have
TBX1 mutations
Issues to be resolved
Is TBX1 the only gene involvedin DiGeorge syndrome?
• Deletion of regulatory elements?• Linked modifier loci?• Chromatin conformational effects?• Linked genes affecting the same tissues?• Exacerbation of haploinsufficiency?
Genetic interactions with linkedgenes
• Crkl gene in 22q11• Sometimes deleted in DGS• Expressed in neural crest• Exacerbated cardiac phenotype in Crkl;
Tbx1 compound mutants
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Genetic interaction Crkl
pharyngeal pouch development as visualized by Pax1 in situ hybridization
Closing in on DiGeorge: HumanSyndromes and Mouse Models
AcknowledgementsColumbia University
Loydie Jerome-MajewskaDebbie ChapmanJeremy Gibson-BrownSarah HancockRobert Kelly
Collaborators Lee Silver Debbie Guris Akira Imamoto