Characterization of 10p Deletions Suggests Two Nonoverlapping Regions Contribute to the DiGeorge Syndrome Phenotype

Gottlieb, Stanley; Driscoll, Deborah A.; Punnett, Hope H.; Sellinger, Beatrice; Emanuel, Beverly S.; Budarf, Marcia L.

doi:10.1086/301718

Cited by 53 publications

(47 citation statements)

References 26 publications

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“…Cleft lip/palate was reported in 2 patients who had an involvement of chromosome 10p [Gottlieg et al, 1998;Lindstrand et al, 2010]. However, the phenotype observed in our patient is different from those previously reported in patients with 10p deletions.…”

Section: Resultscontrasting

confidence: 86%

Cleft Lip/Palate, Short Stature, and Developmental Delay in a Boy with a 5.6-Mb Interstitial Deletion Involving 10p15.3p14

et al. 2015

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The chromosome interval 10p15.3p14 harbors about a dozen genes. This region has been implicated in a few well-known human phenotypes, namely HDR syndrome (hypoparathyroidism, sensorineural deafness, and renal dysplasia) and DGS2 (DiGeorge syndrome 2), but a number of variable phenotypes have also been reported. Cleft lip/palate seems to be a very unusual finding within the clinical spectrum of patients with this deletion. Here, we report a male child born with short stature, cleft lip/palate, and feeding problems who was found to have a 5.6-Mb deletion at 10p15.3p14.

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Section: Resultscontrasting

confidence: 86%

Cleft Lip/Palate, Short Stature, and Developmental Delay in a Boy with a 5.6-Mb Interstitial Deletion Involving 10p15.3p14

et al. 2015

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“…Thus, the Raldh2 neo/Ϫ DGS-like syndrome is likely to result from pharyngeal molecular alterations that may be independent (e.g., Hoxa1 and Hoxb1 deficiency, ref. Despite the frequent occurrence of 22q11.2 deletions in patients with DGS͞VCFS features, DGS has long been recognized as an etiologically heterogeneous syndrome (37), which may involve other genetic loci (such as 10p3) (43,44), as well as epigenetic and͞or environmental causes. Our data, which demonstrate that caudal branchial arches are exquisitely sensitive to RA deficiency, indicate that decreased levels of embryonic RA could be one of these causes.…”

Section: Discussionmentioning

confidence: 99%

Decreased embryonic retinoic acid synthesis results in a DiGeorge syndrome phenotype in newborn mice

Vermot

Niederreither

Garnier

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

146

115

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Retinoic acid (RA), the active derivative of vitamin A, is involved in various developmental and homeostatic processes. To define whether certain developmental events are particularly sensitive to a decrease in embryonic RA levels, we generated mice bearing a hypomorphic allele of the RA-synthesizing enzyme Raldh2. The resulting mutant mice, which die perinatally, exhibit the features of the human DiGeorge syndrome (DGS) with heart outflow tract septation defects and anomalies of the aortic arch-derived head and neck arteries, laryngeal-tracheal cartilage defects, and thymus͞parathyroid aplasia or hypoplasia. Analysis of Raldh2 hypomorph embryos reveal selective defects of the posterior (third to sixth) branchial arches, including absence or hypoplasia of the corresponding aortic arches and pharyngeal pouches, and local down-regulation of RA-target genes. Thus, a decreased level of embryonic RA (through genetic and͞or nutritional causes) could represent a major modifier of the expressivity of human 22q11del-associated DiGeorge͞velocardiofacial syndromes and, if severe enough, could on its own lead to the clinical features of the DiGeorge syndrome.

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“…Foxa proteins are inherently capable of initiating chromatin relaxation events (Cirillo et al 2002) in collaboration with the zincfinger transcription factor GATA4, suggesting a general mechanism for transcriptional activation by Fox proteins. It will be interesting to determine whether Foxa2 similarly cooperates with GATA3 to regulate Tbx1, as GATA3 is coexpressed in the pharyngeal endoderm (Lim et al 2000) and is linked to a second DiGeorge syndrome locus on 10p (Gottlieb et al 1998). …”

Section: Transcriptional Regulation Of Tbx1 By Fox Proteinsmentioning

confidence: 99%

Tbx1is regulated by tissue-specific forkhead proteins through a common Sonic hedgehog-responsive enhancer

Yamagishi¹,

Maeda²,

Hu³

et al. 2003

Genes Dev.

245

212

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Haploinsufficiency of Tbx1 is likely a major determinant of cardiac and craniofacial birth defects associated with DiGeorge syndrome. Although mice deficient in Tbx1 exhibit pharyngeal and aortic arch defects, the developmental program and mechanisms through which Tbx1 functions are relatively unknown. We identified a single cis-element upstream of Tbx1 that recognized winged helix/forkhead box (Fox)-containing transcription factors and was essential for regulation of Tbx1 transcription in the pharyngeal endoderm and head mesenchyme. The Tbx1 regulatory region was responsive to signaling by Sonic hedgehog (Shh) in vivo. We show that Shh is necessary for aortic arch development, similar to Tbx1, and is also required for expression of Foxa2 and Foxc2 in the pharyngeal endoderm and head mesenchyme, respectively. Foxa2, Foxc1, or Foxc2 could bind and activate transcription through the critical cis-element upstream of Tbx1, and Foxc proteins were required, within their expression domains, for Tbx1 transcription in vivo. We propose that Tbx1 is a direct transcriptional target of Fox proteins and that Fox proteins may serve an intermediary role in Shh regulation of Tbx1.

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Characterization of 10p Deletions Suggests Two Nonoverlapping Regions Contribute to the DiGeorge Syndrome Phenotype

Cited by 53 publications

References 26 publications

Cleft Lip/Palate, Short Stature, and Developmental Delay in a Boy with a 5.6-Mb Interstitial Deletion Involving 10p15.3p14

Cleft Lip/Palate, Short Stature, and Developmental Delay in a Boy with a 5.6-Mb Interstitial Deletion Involving 10p15.3p14

Decreased embryonic retinoic acid synthesis results in a DiGeorge syndrome phenotype in newborn mice

Tbx1is regulated by tissue-specific forkhead proteins through a common Sonic hedgehog-responsive enhancer

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