Dataset Information

When half is not enough: gene expression and dosage in the 22q11 deletion syndrome.

ABSTRACT: The 22q11 Deletion Syndrome (22q11DS, also known as DiGeorge or Velo-Cardio-Facial Syndrome) has a variable constellation of phenotypes including life-threatening cardiac malformations, craniofacial, limb, and digit anomalies, a high incidence of learning, language, and behavioral disorders, and increased vulnerability for psychiatric diseases, including schizophrenia. There is still little clear understanding of how heterozygous microdeletion of approximately 30-50 genes on chromosome 22 leads to this diverse spectrum of phenotypes, especially in the brain. Three possibilities exist: 1) 22q11DS may reflect haploinsufficiency, homozygous loss of function, or heterozygous gain of function of a single gene within the deleted region; 2) 22q11DS may result from haploinsufficiency, homozygous loss of function, or heterozygous gain of function of a few genes in the deleted region acting at distinct phenotypically compromised sites; 3) 22q11DS may reflect combinatorial effects of reduced dosage of multiple genes acting in concert at all phenotypically compromised sites. Here, we consider evidence for each of these possibilities. Our review of the literature, as well as interpretation of work from our laboratory, favors the third possibility: 22q11DS reflects diminished expression of multiple 22q11 genes acting on common cellular processes during brain as well as heart, face, and limb development, and subsequently in the adolescent and adult brain.

SUBMITTER: Meechan DW

PROVIDER: S-EPMC6032457 | biostudies-other | 2007

REPOSITORIES: biostudies-other

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When half is not enough: gene expression and dosage in the 22q11 deletion syndrome.

Meechan D W DW Maynard T M TM Gopalakrishna D D Wu Y Y LaMantia A S AS

Gene expression 20070101 6

The 22q11 Deletion Syndrome (22q11DS, also known as DiGeorge or Velo-Cardio-Facial Syndrome) has a variable constellation of phenotypes including life-threatening cardiac malformations, craniofacial, limb, and digit anomalies, a high incidence of learning, language, and behavioral disorders, and increased vulnerability for psychiatric diseases, including schizophrenia. There is still little clear understanding of how heterozygous microdeletion of approximately 30-50 genes on chromosome 22 leads ...[more]

PMID: 17708416

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Project description:Rationale: 22q11 deletion syndrome arises from recombination between low copy repeats on chromosome 22. Typical deletions result in hemizygosity for TBX1 associated with congenital cardiovascular disease. Deletions distal to the typically deleted region result in a similar cardiac phenotype but lack extra-cardiac features of the syndrome suggesting that a second haploinsufficient gene maps to this interval. Objective: The transcription factor HIC2 is lost in most distal deletions as well as a minority of typical deletions. We used mouse models to test the hypothesis that HIC2 hemizygosity causes congenital heart disease. Methods and Results: We created a genetrap mouse allele of Hic2. The genetrap reporter was expressed in the heart throughout the key stages of cardiac morphogenesis. Homozygosity for the genetrap allele was embryonic lethal before embryonic day E10.5 while the heterozygous condition exhibited a partially penetrant late lethality. One third of heterozygous embryos had a cardiac phenotype. Magnetic resonance imaging demonstrated a ventricular septal defect with overriding aorta. Conditional targeting indicated a requirement for Hic2 within the Nkx2.5+ and Mesp1+ cardiovascular progenitor lineages but not in the Wnt1+ neural crest or Mef2c+ second heart field lineages. Microarray analysis revealed increased expression of BMP10. Conclusions: Our results demonstrate a novel role for Hic2 in cardiac development. Hic2 is the first gene within the distal 22q11 interval to have a demonstrated haploinsufficient cardiac phenotype in mice. Together our data suggests HIC2 haploinsufficiency likely contributes to the cardiac defects seen in distal 22q11 deletion syndrome. The aim of this microarray experiment was to compare gene expression changes in the E13.5 mouse heart in a conditional knockout of Hic2 (Mesp1Cre/+; Hic2FL/FL) against control. All samples represent pools of isolated hearts from E13.5 mouse embryos. 3 replicates of each genotype were assayed. The genotypes are: 'WT' (Hic2FL/FL) 'KO' (Mesp1Cre/+; Hic2 FL/FL)

Dataset Information

When half is not enough: gene expression and dosage in the 22q11 deletion syndrome.

Publications

When half is not enough: gene expression and dosage in the 22q11 deletion syndrome.

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