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Congenital heart disease is the leading cause of birth defects, affecting 9 out of 1000 newborns each year. A particularly severe form of congenital heart disease is heterotaxy, a disorder of left-right development. Despite aggressive surgical management, patients with heterotaxy have poor survival rates and severe morbidity due to their complex congenital heart disease. Recent genetic analysis of affected patients has found novel candidate genes for heterotaxy although their underlying mechanisms remain unknown. In this review, we discuss the importance and challenges of birth defects research including high locus heterogeneity and few second alleles that make defining disease causality difficult. A powerful strategy moving forward is to analyze these candidate genes in a high-throughput human disease model. Xenopus is ideal for these studies. We present multiple examples demonstrating the power of Xenopus in discovering new biology from the analysis of candidate heterotaxy genes such as GALNT11, NEK2 and BCOR. These genes have diverse roles in embryos and have led to a greater understanding of complex signaling pathways and basic developmental biology. It is our hope that the mechanistic analysis of these candidate genes in Xenopus enabled by next generation sequencing of patients will provide clinicians with a greater understanding of patient pathophysiology allowing more precise and personalized medicine, to help patients more effectively in the future.
Fig. 1. Ciliary flow and signaling in the gastrocel roof plate (GRP) of the frog.
-The black dashed line outlines the GRP. The red lines represent the inner motile cilia, and the green and purple represent the outer immotile cili The blue arrows show the leftward fluid flow across the GRP that is produced by the motile cilia and sensed by the immotile cili.
-coco is initially expressed bilaterally. Ciliary flow reduces the expression of coco on the left side. Coco inactivates Nodal on the left, which leads to pitx2c expression on the left side of the embryo and ultimately plays a role in organ situs and asymmetric development.
Fig. 2. Model for patient centered gene discovery, analysis and ultimately personalized medicine.
This model highlights how DNA can be taken from a patient with congenital heart disease. His or her genome can then be sequeneced, and geneticists can analyze it for likely causative mutations. Embyologists can then use Xenopus as a model system to understand gene function. This knowledge can then be taken back to the patient in order to personalize medicine.
Abu-Issa,
Patterning of the heart field in the chick.
2008, Pubmed
Abu-Issa,
Patterning of the heart field in the chick.
2008,
Pubmed
Afzelius,
A human syndrome caused by immotile cilia.
1976,
Pubmed
Amula,
Heterotaxy syndrome: impact of ventricular morphology on resource utilization.
2014,
Pubmed
Bahe,
Rootletin forms centriole-associated filaments and functions in centrosome cohesion.
2005,
Pubmed
Bajpai,
CHD7 cooperates with PBAF to control multipotent neural crest formation.
2010,
Pubmed
,
Xenbase
Basu,
Cilia multifunctional organelles at the center of vertebrate left-right asymmetry.
2008,
Pubmed
,
Xenbase
Bennett,
Control of mucin-type O-glycosylation: a classification of the polypeptide GalNAc-transferase gene family.
2012,
Pubmed
Bhattacharya,
CRISPR/Cas9: An inexpensive, efficient loss of function tool to screen human disease genes in Xenopus.
2015,
Pubmed
,
Xenbase
Blum,
Xenopus, an ideal model system to study vertebrate left-right asymmetry.
2009,
Pubmed
,
Xenbase
Boskovski,
The heterotaxy gene GALNT11 glycosylates Notch to orchestrate cilia type and laterality.
2013,
Pubmed
,
Xenbase
Brueckner,
Heterotaxia, congenital heart disease, and primary ciliary dyskinesia.
2007,
Pubmed
Davis,
The chirality of gut rotation derives from left-right asymmetric changes in the architecture of the dorsal mesentery.
2008,
Pubmed
Deblandre,
A two-step mechanism generates the spacing pattern of the ciliated cells in the skin of Xenopus embryos.
1999,
Pubmed
,
Xenbase
Endicott,
The NIMA-like kinase Nek2 is a key switch balancing cilia biogenesis and resorption in the development of left-right asymmetry.
2015,
Pubmed
,
Xenbase
Fakhro,
Rare copy number variations in congenital heart disease patients identify unique genes in left-right patterning.
2011,
Pubmed
,
Xenbase
Fry,
The NIMA-related kinase X-Nek2B is required for efficient assembly of the zygotic centrosome in Xenopus laevis.
2000,
Pubmed
,
Xenbase
Hamada,
Mechanisms of left-right asymmetry and patterning: driver, mediator and responder.
2014,
Pubmed
Heron,
Deaths: final data for 2006.
2009,
Pubmed
Hilton,
Left-sided embryonic expression of the BCL-6 corepressor, BCOR, is required for vertebrate laterality determination.
2007,
Pubmed
,
Xenbase
Kaltenbrun,
Xenopus: An emerging model for studying congenital heart disease.
2011,
Pubmed
,
Xenbase
Kato,
The multiple roles of Notch signaling during left-right patterning.
2011,
Pubmed
Kawasumi,
Left-right asymmetry in the level of active Nodal protein produced in the node is translated into left-right asymmetry in the lateral plate of mouse embryos.
2011,
Pubmed
Kirk,
Mutations in cardiac T-box factor gene TBX20 are associated with diverse cardiac pathologies, including defects of septation and valvulogenesis and cardiomyopathy.
2007,
Pubmed
Krebs,
Notch signaling regulates left-right asymmetry determination by inducing Nodal expression.
2003,
Pubmed
Kurpios,
The direction of gut looping is established by changes in the extracellular matrix and in cell:cell adhesion.
2008,
Pubmed
Laurell,
Phosphorylation of Nup98 by multiple kinases is crucial for NPC disassembly during mitotic entry.
2011,
Pubmed
Lee,
Morphogenesis of the node and notochord: the cellular basis for the establishment and maintenance of left-right asymmetry in the mouse.
2008,
Pubmed
Lin,
Laterality defects in the national birth defects prevention study (1998-2007): birth prevalence and descriptive epidemiology.
2014,
Pubmed
Lopes,
Notch signalling regulates left-right asymmetry through ciliary length control.
2010,
Pubmed
MacDorman,
Fetal and Perinatal Mortality: United States, 2013.
2015,
Pubmed
Mandel,
The BMP pathway acts to directly regulate Tbx20 in the developing heart.
2010,
Pubmed
,
Xenbase
Marino,
Neurodevelopmental outcomes in children with congenital heart disease: evaluation and management: a scientific statement from the American Heart Association.
2012,
Pubmed
Martin,
Annual summary of vital statistics--2003.
2005,
Pubmed
McGrath,
Two populations of node monocilia initiate left-right asymmetry in the mouse.
2003,
Pubmed
Mussatto,
Risk and prevalence of developmental delay in young children with congenital heart disease.
2014,
Pubmed
Ng,
Oculofaciocardiodental and Lenz microphthalmia syndromes result from distinct classes of mutations in BCOR.
2004,
Pubmed
Nonaka,
Determination of left-right patterning of the mouse embryo by artificial nodal flow.
2002,
Pubmed
Okada,
Mechanism of nodal flow: a conserved symmetry breaking event in left-right axis determination.
2005,
Pubmed
Raya,
Notch activity acts as a sensor for extracellular calcium during vertebrate left-right determination.
2004,
Pubmed
Rigler,
Novel copy-number variants in a population-based investigation of classic heterotaxy.
2015,
Pubmed
Sakano,
BCL6 canalizes Notch-dependent transcription, excluding Mastermind-like1 from selected target genes during left-right patterning.
2010,
Pubmed
,
Xenbase
Schweickert,
The nodal inhibitor Coco is a critical target of leftward flow in Xenopus.
2010,
Pubmed
,
Xenbase
Singh,
Tbx20 interacts with smads to confine tbx2 expression to the atrioventricular canal.
2009,
Pubmed
Stalsberg,
The precardiac areas and formation of the tubular heart in the chick embryo.
1969,
Pubmed
Stillbirth Collaborative Research Network Writing Group,
Causes of death among stillbirths.
2011,
Pubmed
Swisher,
Increased postoperative and respiratory complications in patients with congenital heart disease associated with heterotaxy.
2011,
Pubmed
Tabin,
A two-cilia model for vertebrate left-right axis specification.
2003,
Pubmed
Takeuchi,
Baf60c is a nuclear Notch signaling component required for the establishment of left-right asymmetry.
2007,
Pubmed
Tanaka,
A potential molecular pathogenesis of cardiac/laterality defects in Oculo-Facio-Cardio-Dental syndrome.
2014,
Pubmed
,
Xenbase
Vissers,
Mutations in a new member of the chromodomain gene family cause CHARGE syndrome.
2004,
Pubmed
Vonica,
The left-right axis is regulated by the interplay of Coco, Xnr1 and derrière in Xenopus embryos.
2007,
Pubmed
,
Xenbase
Waitzman,
Estimates of the economic costs of birth defects.
1994,
Pubmed
Wallingford,
Xenopus.
2010,
Pubmed
,
Xenbase
Warkman,
Xenopus as a model system for vertebrate heart development.
2007,
Pubmed
,
Xenbase
Warnes,
Task force 1: the changing profile of congenital heart disease in adult life.
2001,
Pubmed
Yoon,
Contribution of birth defects and genetic diseases to pediatric hospitalizations. A population-based study.
1997,
Pubmed
Zaidi,
De novo mutations in histone-modifying genes in congenital heart disease.
2013,
Pubmed
Zhu,
Genetics of human heterotaxias.
2006,
Pubmed
van der Bom,
The changing epidemiology of congenital heart disease.
2011,
Pubmed
van der Linde,
Birth prevalence of congenital heart disease worldwide: a systematic review and meta-analysis.
2011,
Pubmed
