Genome-wide identification of mouse congenital heart disease loci

Kamp, Anna; Peterson, Michael A.; Svenson, Karen L.; Bjork, Bryan C.; Hentges, Kathryn E.; Rajapaksha, Tharinda W.; Moran, Jennifer L.; Justice, Monica J.; Seidman, J. G.; Seidman, Christine E.; Moskowitz, Ivan P.; Beier, David R.

doi:10.1093/hmg/ddq211

Cited by 18 publications

(21 citation statements)

References 39 publications

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“…4a ). We then examined the Dync2h1 lln phenotype when combined with avc1 , a partial loss-of-function allele of Ift172 29 , 30 . While neural patterning in Ift172 avc1/avc1 mutants was nearly wild type ( Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Complex interactions between genes controlling trafficking in primary cilia

et al. 2011

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Cilia-associated human genetic disorders are striking in the diversity of their abnormalities and their complex inheritance. Inactivation of the retrograde ciliary motor by mutations in DYNC2H1 cause skeletal dysplasias that have strongly variable expressivity. Here we define unexpected genetic relationships between Dync2h1 and other genes required for ciliary trafficking. Mutations in mouse Dync2h1 disrupt cilia structure, block Sonic hedgehog (Shh) signaling and cause midgestation lethality. Heterozygosity for Ift172, a gene required for anterograde ciliary trafficking, suppresses the cilia phenotypes, Shh signaling defects and early lethality of Dync2h1 homozygotes. Ift122, like Dync2h1, is required for retrograde ciliary trafficking, but reduction of the Ift122 gene dosage also suppresses the Dync2h1 phenotype. These genetic interactions illustrate the cell biology underlying ciliopathies and argue that mutations in IFT genes cause their phenotypes because of their roles in cilia architecture rather than direct roles in signaling.

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Section: Resultsmentioning

confidence: 99%

Complex interactions between genes controlling trafficking in primary cilia

et al. 2011

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“…Moreover, with identification of fetuses with CHD by ultrasound, we could exercise more caution in recovering stillborn pups, which otherwise might be cannibalized by the mother. We note another study screened for CHD mutants in a mouse mutagenesis screen with postnatal collection of stillborn pups and conducting phenotyping by histopathology 14 . While CHD mutants can be recovered in this manner, it is not high throughput and a significant fraction of the CHD mutants would be missed.…”

Section: Discussionmentioning

confidence: 99%

Interrogating Congenital Heart Defects With Noninvasive Fetal Echocardiography in a Mouse Forward Genetic Screen

Liu

Francis

Kim

et al. 2014

Circ: Cardiovascular Imaging

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Background Congenital heart disease (CHD) has a multifactorial etiology, but a genetic contribution is indicated by heritability studies. To investigate the spectrum of CHD with a genetic etiology, we conducted a forward genetic screen in inbred mice using fetal echocardiography to recover mutants with CHD. Mice are ideally suited for these studies, given they have the same four-chamber cardiac anatomy that is the substrate for CHD. Methods and Results Ethylnitrosourea mutagenized mice were ultrasound interrogated by fetal echocardiography using a clinical ultrasound system, and fetuses suspected to have cardiac abnormalities were further interrogated with an ultra-high frequency ultrasound biomicroscopy (UBM). Scanning of 46,270 fetuses revealed 1,722 with cardiac anomalies, with 27.9% dying prenatally. Most of the structural heart defects can be diagnosed using the UBM, but not with the clinical ultrasound system. Confirmation with analysis by necropsy and histopathology showed excellent diagnostic capability of UBM for most CHD. Ventricular septal defect was the most common CHD observed, while outflow tract and atrioventricular septal defects were the most prevalent complex CHD. Cardiac/visceral organ situs defects were observed at surprisingly high incidence. The rarest CHD found was hypoplastic left heart syndrome (HLHS), a phenotype never seen in mice previously. Conclusions We developed a high throughput two-tier ultrasound phenotyping strategy for efficient recovery of even rare CHD phenotypes, including the first mouse models of HLHS. Our findings support a genetic etiology for a wide spectrum of CHD and suggest the disruption of left-right patterning may play an important role in CHD.

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“…Cardiovascular and pulmonary defects often become evident after birth as a result of the transition from fetal to neonatal circulation (Kamp et al, 2010). A number of recent studies found epigenetic modifiers to be important in controlling cardiac maturation and differentiation (Conway et al, 2003;Chang and Bruneau, 2012).…”

Section: Rlf Mutants Display Defects In Cardiac Developmentmentioning

confidence: 99%