Martina Brueckner, MD
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Research Summary
The goal of our work is to determine the genetic cause and developmental mechanisms underlying congenital heart disease and, in particular, the function of cilia in heart development. The research aims to bridge research in the basic developmental biology mechanisms underlying development of the embryonic left-right axis with clinical pediatric cardiology and cardiac genetics. The laboratory has been integral in understanding the cellular and molecular mechanism underlying vertebrate LR asymmetry, beginning with the discovery that the axonemal dynein left-right dynein is essential for the development of vertebrate left-right asymmetry. We then demonstrated that a combination of motile and immotile cilia establishes an early asymmetric calcium signal that is essential to normal LR development of the heart. As part of the Pediatric Cardiac Genomics Consortium (PCGC), we are now combining our understanding of the basic biology underlying left-right development with state-of-the-art genomics to a more comprehensive understanding of human congenital disease, in particular, human heterotaxy. We are focusing on the ability to directly test putative genetic causes of human CHD identified from genomic analysis of patient DNA in animal model systems including mouse and zebrafish.
Although our medical and surgical management of patients with congenital heart disease has made tremendous progress in the past 25 years, the understanding of why CHD develops remains relatively limited. One challenge in the care of patients with CHD is that different patients with anatomically very similar disease can have greatly disparate long-term outcomes. The mechanism underlying any individual patient’s CHD may have as of yet unknown impact on how well they do, and it is hoped that eventually it will become possible to tailor medical management and surgery more specifically based on an individual’s combination of anatomical abnormality and underlying developmental defect. If ciliary defects are responsible for some human CHD, it may become possible to treat the later manifestations of the disease, such as progressive cardiac valve dysfunction observed in many adult patients who have had successful surgery for their CHD, with drugs aimed at restoring more normal ciliary signaling.
Specialized Terms: Development of left-right asymmetry; Heterotaxy syndrome; Kartagener syndrome; Situs inversus
Extensive Research Description
The current research foci of the Brueckner Lab are:
1. Understanding the cellular and molecular mechanism underlying vertebrate LR asymmetry
My laboratory first discovered that the axonemal dynein left-right dynein (lrd) is essential for the development of vertebrate left-right asymmetry (Supp et al, Nature 1997). Lrd powers directional beating of cilia at the left-right organizer and breaks bilateral symmetry by creating directional flow of extraembryonic fluid. Importantly, in a collaboration with the labs of Clifford Tabin and H. Joseph Yost, we identified that the ciliated left-right organizer is conserved throughout vertebrates (Essner et al, Nature, 2002); this observation has allowed us to move seamlessly between model organism systems including mouse and zebrafish for our continuing work on left-right development. My laboratory then addressed the question of how directional flow is sensed to connect cilia motility to asymmetric organogenesis. We demonstrated that polycystin-2 containing immotile cilia sense directional flow to initiate asymmetric signaling linking the events at the left-right organizer with subsequent asymmetric gene expression and heart development (McGrath et al, Cell 2003). In order to address the question of the molecular mechanism by which polycystin initiates asymmetric signaling in response to directional flow of extraembryonic fluid, we then developed a method to target genetically-encoded calcium indicators specifically into cilia in living embryos. This approach allowed us to see asymmetric, polycystin2-dependent intraciliary calcium waves at the left-right organizer of living zebrafish that are the earliest molecular asymmetry in the vertebrate embryo (Yuan et al, Current Biology, 2015). We are continuing to develop technology to permit live imaging of intraciliary calcium in zebrafish and mouse embryos (Yuan and Brueckner, Methods Mol Bio, 2016). Current work is focused on the link between calcium signaling and asymmetric organ development utilizing genetically encoded calcium reporters targeted to cilia in embryos and cultured cells. We are testing the hypothesis that mechanical stimuli trigger intraciliary calcium via the polycystin complex, and that asymmetric calcium is determinative for the development of left-right asymmetry. In addition, we are exploring the potential role of the Ankyrin-repeat protein Inversin as a link between intraciliary calcium and asymmetric molecular signaling. Finally, we are exploring the role of intracardiac cilia in heart development where we propose that they also function as mechanosensors, but now integrate mechanical signals such as contractile and hemodynamic forces with transcriptional control of cardiac morphogenesis.
2. Understanding the genetic architecture of congenital heart disease
The question remains, however, how understanding the novel and remarkable mechanism by which cilia drive left-right and cardiac development connects to patients with congenital heart disease. To this end, we have established collaboration with Richard Lifton and the Yale Center for Genome Analysis, and have become part of the Pediatric Cardiac Genomics Consortium (PCGC). We began by showing that copy-number variations underlie ~10-15% of human heterotaxy (Fakhro et al, PNAS, 2011). The PCGC has recruited ~13,000 patients with CHD so far and aims to apply current genomic approaches in order to develop a more global understanding of the genetics of congenital heart disease. The initial analysis of 362 patients with severe CHD demonstrated that de-novo mutations underlie ~10% of CHD, and implicated chromatin remodeling as a heretofore unrecognized molecular mechanism in CHD (Zaidi et al, Nature, 2013). Expansion of the sequenced patient cohort to over 1,100 patients showed a link between the genetic cause of CHD and neurodevelopmental outcome (Homsey et al, Science, 2015). Analysis of mutations identified from CHD patients has already lead us to new insights into the mechanism of early heart development, including how the glycosylation enzyme GALNT11 modulates NOTCH signaling in determining cilia identity in the development of LR asymmetry (Boskovski et al, Nature, 2013), and how the NIMA-like kinase Nek2 balances ciliogenesis and resorption (Endicott et al, Development, 2015). Finally, increasing the size of the studied CHD cohort coupled with a novel computational approach for the first time allowed the unbiased identification of inherited variants contributing to human disease, and identified that mutations affecting cilia genes contribute directly to human CHD (Jin et al, Nature Genetics, 2017). Work is ongoing to begin to connect genotype with clinical outcome and reconnect the developmental biology work with clinical pediatric cardiology.
Current work is focused on expanding the understanding of the genetic underpinnings of congenital heart disease through large-scale genomic analyses of patients with CHD, including exploration of inherited contributions to CHD, and potential multigenic inheritance.
3. The role of Chromatin regulation in cilia and cardiac development.
Exome sequencing of 2,426 parent-offspring trios with severe CHD in the offspring identified a highly significant excess of de-novo dominant mutations in chromatin remodeling genes including 11 patients with mutations affecting monoubiquitylation of Histone H2BK120. The mechanisms linking mutation to disease are unknown. In our preliminary work, knockdown of five CHD-associated chromatin remodeling genes in Xenopus produced an entirely unexpected phenotype: in addition to abnormal cardiac development, cilia structure and/or motility were abnormal. This mirrored the phenotype of a patient with mutation in RNF20, who had Htx and primary ciliary dyskinesia (PCD) with absent inner dynein arms (Robson et al, PNAS, 2019). RNF20 is an E3 ubiquitin ligase that ubiquitylates H2BK120. Rnf20 has previously been implicated in differentiation of embryonic stem cells; however, there is no known role for RNF20 and H2BK120 ubiquitylation in ciliary biology, LR patterning, or cardiac development. These observations raise the question why haploinsufficiency for ubiquitously required epigenetic regulation affects heart development, and cilia function, in particular. We propose that RNF20 functions in cardiac development first through control of the transcriptional program directing cilia biogenesis and LR patterning, and then through direct function in the heart. Current experiments are testing the mechanism of Rnf20-mediated H2BK120 ubiquitylation in mouse embryos and cultured cardiomyocytes using ChIPseq and RNAseq analyses.
Coauthors
Research Interests
Cardiology; Genetics; Heart Diseases; Kartagener Syndrome; Situs Inversus; Heterotaxy Syndrome
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Selected Publications
- Inactivation of Invs/Nphp2 in renal epithelial cells drives infantile nephronophthisis like phenotypes in mouseLi Y, Xu W, Makova S, Brueckner M, Sun Z. Inactivation of Invs/Nphp2 in renal epithelial cells drives infantile nephronophthisis like phenotypes in mouse ELife 2023, 12: e82395. PMID: 36920028, PMCID: PMC10154023, DOI: 10.7554/elife.82395.
- Cilia function as calcium-mediated mechanosensors that instruct left-right asymmetryDjenoune L, Mahamdeh M, Truong T, Nguyen C, Fraser S, Brueckner M, Howard J, Yuan S. Cilia function as calcium-mediated mechanosensors that instruct left-right asymmetry Science 2023, 379: 71-78. PMID: 36603098, PMCID: PMC9939240, DOI: 10.1126/science.abq7317.
- Association of Potentially Damaging De Novo Gene Variants With Neurologic Outcomes in Congenital Heart DiseaseMorton S, Norris-Brilliant A, Cunningham S, King E, Goldmuntz E, Brueckner M, Miller T, Thomas N, Liu C, Adams H, Bellinger D, Cleveland J, Cnota J, Dale A, Frommelt M, Gelb B, Grant P, Goldberg C, Huang H, Kuperman J, Li J, McQuillen P, Panigrahy A, Porter G, Roberts A, Russell M, Seidman C, Tivarus M, Anagnoustou E, Hagler D, Chung W, Newburger J. Association of Potentially Damaging De Novo Gene Variants With Neurologic Outcomes in Congenital Heart Disease JAMA Network Open 2023, 6: e2253191. PMID: 36701153, PMCID: PMC9880793, DOI: 10.1001/jamanetworkopen.2022.53191.
- Network assisted analysis of de novo variants using protein-protein interaction information identified 46 candidate genes for congenital heart diseaseXie Y, Jiang W, Dong W, Li H, Jin SC, Brueckner M, Zhao H. Network assisted analysis of de novo variants using protein-protein interaction information identified 46 candidate genes for congenital heart disease PLOS Genetics 2022, 18: e1010252. PMID: 35671298, PMCID: PMC9205499, DOI: 10.1371/journal.pgen.1010252.
- Quantifying concordant genetic effects of de novo mutations on multiple disordersGuo H, Hou L, Shi Y, Jin SC, Zeng X, Li B, Lifton R, Brueckner M, Zhao H, Lu Q. Quantifying concordant genetic effects of de novo mutations on multiple disorders ELife 2022, 11: e75551. PMID: 35666111, PMCID: PMC9217133, DOI: 10.7554/elife.75551.
- Mutation spectrum of congenital heart disease in a consanguineous Turkish populationDong W, Kaymakcalan H, Jin SC, Diab NS, Tanıdır C, Yalcin ASY, Ercan‐Sencicek A, Mane S, Gunel M, Lifton RP, Bilguvar K, Brueckner M. Mutation spectrum of congenital heart disease in a consanguineous Turkish population Molecular Genetics & Genomic Medicine 2022, 10: e1944. PMID: 35481623, PMCID: PMC9184665, DOI: 10.1002/mgg3.1944.
- Neither cardiac mitochondrial DNA variation nor copy number contribute to congenital heart disease riskWillcox JAL, Geiger JT, Morton SU, McKean D, Quiat D, Gorham JM, Tai AC, DePalma S, Bernstein D, Brueckner M, Chung WK, Giardini A, Goldmuntz E, Kaltman JR, Kim R, Newburger JW, Shen Y, Srivastava D, Tristani-Firouzi M, Gelb B, Porter GA, Seidman JG, Seidman CE. Neither cardiac mitochondrial DNA variation nor copy number contribute to congenital heart disease risk American Journal Of Human Genetics 2022, 109: 961-966. PMID: 35397206, PMCID: PMC9118105, DOI: 10.1016/j.ajhg.2022.03.011.
- Genome-Wide De Novo Variants in Congenital Heart Disease Are Not Associated With Maternal Diabetes or ObesityMorton SU, Pereira AC, Quiat D, Richter F, Kitaygorodsky A, Hagen J, Bernstein D, Brueckner M, Goldmuntz E, Kim RW, Lifton RP, Porter GA, Tristani-Firouzi M, Chung WK, Roberts A, Gelb BD, Shen Y, Newburger JW, Seidman JG, Seidman CE. Genome-Wide De Novo Variants in Congenital Heart Disease Are Not Associated With Maternal Diabetes or Obesity Circulation Genomic And Precision Medicine 2022, 15: e003500. PMID: 35130025, PMCID: PMC9295870, DOI: 10.1161/circgen.121.003500.
- A change of heart: new roles for cilia in cardiac development and diseaseDjenoune L, Berg K, Brueckner M, Yuan S. A change of heart: new roles for cilia in cardiac development and disease Nature Reviews Cardiology 2021, 19: 211-227. PMID: 34862511, PMCID: PMC10161238, DOI: 10.1038/s41569-021-00635-z.
- Molecular Genetics and Complex Inheritance of Congenital Heart DiseaseDiab NS, Barish S, Dong W, Zhao S, Allington G, Yu X, Kahle KT, Brueckner M, Jin SC. Molecular Genetics and Complex Inheritance of Congenital Heart Disease Genes 2021, 12: 1020. PMID: 34209044, PMCID: PMC8307500, DOI: 10.3390/genes12071020.
- Association of Damaging Variants in Genes With Increased Cancer Risk Among Patients With Congenital Heart DiseaseMorton SU, Shimamura A, Newburger PE, Opotowsky AR, Quiat D, Pereira AC, Jin SC, Gurvitz M, Brueckner M, Chung WK, Shen Y, Bernstein D, Gelb BD, Giardini A, Goldmuntz E, Kim RW, Lifton RP, Porter GA, Srivastava D, Tristani-Firouzi M, Newburger JW, Seidman JG, Seidman CE. Association of Damaging Variants in Genes With Increased Cancer Risk Among Patients With Congenital Heart Disease JAMA Cardiology 2021, 6: 457-462. PMID: 33084842, PMCID: PMC7578917, DOI: 10.1001/jamacardio.2020.4947.
- Mechanisms of Congenital Heart Disease Caused by NAA15 HaploinsufficiencyWard T, Tai W, Morton S, Impens F, Van Damme P, Van Haver D, Timmerman E, Venturini G, Zhang K, Jang MY, Willcox JAL, Haghighi A, Gelb BD, Chung WK, Goldmuntz E, Porter GA, Lifton R, Brueckner M, Yost HJ, Bruneau BG, Gorham J, Kim Y, Pereira A, Homsy J, Benson CC, DePalma SR, Varland S, Chen CS, Arnesen T, Gevaert K, Seidman C, Seidman JG. Mechanisms of Congenital Heart Disease Caused by NAA15 Haploinsufficiency Circulation Research 2021, 128: 1156-1169. PMID: 33557580, PMCID: PMC8048381, DOI: 10.1161/circresaha.120.316966.
- Integrative modeling of transmitted and de novo variants identifies novel risk genes for congenital heart disease.Li M, Zeng X, Jin C, Jin SC, Dong W, Brueckner M, Lifton R, Lu Q, Zhao H. Integrative modeling of transmitted and de novo variants identifies novel risk genes for congenital heart disease. Quantitative Biology 2021, 9: 216-227. PMID: 35414959, PMCID: PMC9000521, DOI: 10.15302/j-qb-021-0248.
- De novo Damaging Variants, Clinical Phenotypes and Post-Operative Outcomes in Congenital Heart DiseaseBoskovski MT, Homsy J, Nathan M, Sleeper LA, Morton S, Manheimer KB, Tai A, Gorham J, Lewis M, Swartz M, Alfieris GM, Bacha EA, Karimi M, Meyer D, Nguyen K, Bernstein D, Romano-Adesman A, Porter GA, Goldmuntz E, Chung WK, Srivastava D, Kaltman JR, Tristani-Firouzi M, Lifton R, Roberts AE, Gaynor JW, Gelb BD, Kim R, Seidman JG, Brueckner M, Mayer JE, Newburger JW, Seidman CE. De novo Damaging Variants, Clinical Phenotypes and Post-Operative Outcomes in Congenital Heart Disease Circulation Genomic And Precision Medicine 2020, 13: e002836-e002836. PMID: 32812804, PMCID: PMC7439931, DOI: 10.1161/circgen.119.002836.
- Genomic analyses implicate noncoding de novo variants in congenital heart diseaseRichter F, Morton SU, Kim SW, Kitaygorodsky A, Wasson LK, Chen KM, Zhou J, Qi H, Patel N, DePalma SR, Parfenov M, Homsy J, Gorham JM, Manheimer KB, Velinder M, Farrell A, Marth G, Schadt EE, Kaltman JR, Newburger JW, Giardini A, Goldmuntz E, Brueckner M, Kim R, Porter GA, Bernstein D, Chung WK, Srivastava D, Tristani-Firouzi M, Troyanskaya OG, Dickel DE, Shen Y, Seidman JG, Seidman CE, Gelb BD. Genomic analyses implicate noncoding de novo variants in congenital heart disease Nature Genetics 2020, 52: 769-777. PMID: 32601476, PMCID: PMC7415662, DOI: 10.1038/s41588-020-0652-z.
- EM-mosaic detects mosaic point mutations that contribute to congenital heart diseaseHsieh A, Morton SU, Willcox JAL, Gorham JM, Tai AC, Qi H, DePalma S, McKean D, Griffin E, Manheimer KB, Bernstein D, Kim RW, Newburger JW, Porter GA, Srivastava D, Tristani-Firouzi M, Brueckner M, Lifton RP, Goldmuntz E, Gelb BD, Chung WK, Seidman CE, Seidman JG, Shen Y. EM-mosaic detects mosaic point mutations that contribute to congenital heart disease Genome Medicine 2020, 12: 42. PMID: 32349777, PMCID: PMC7189690, DOI: 10.1186/s13073-020-00738-1.
- De novo damaging variants associated with congenital heart diseases contribute to the connectomeJi W, Ferdman D, Copel J, Scheinost D, Shabanova V, Brueckner M, Khokha MK, Ment LR. De novo damaging variants associated with congenital heart diseases contribute to the connectome Scientific Reports 2020, 10: 7046. PMID: 32341405, PMCID: PMC7184603, DOI: 10.1038/s41598-020-63928-2.
- Systems Analysis Implicates WAVE2 Complex in the Pathogenesis of Developmental Left-Sided Obstructive Heart DefectsEdwards JJ, Rouillard AD, Fernandez NF, Wang Z, Lachmann A, Shankaran SS, Bisgrove BW, Demarest B, Turan N, Srivastava D, Bernstein D, Deanfield J, Giardini A, Porter G, Kim R, Roberts AE, Newburger JW, Goldmuntz E, Brueckner M, Lifton RP, Seidman CE, Chung WK, Tristani-Firouzi M, Yost HJ, Ma’ayan A, Gelb BD. Systems Analysis Implicates WAVE2 Complex in the Pathogenesis of Developmental Left-Sided Obstructive Heart Defects JACC Basic To Translational Science 2020, 5: 376-386. PMID: 32368696, PMCID: PMC7188873, DOI: 10.1016/j.jacbts.2020.01.012.
- De novo and recessive forms of congenital heart disease have distinct genetic and phenotypic landscapesWatkins WS, Hernandez EJ, Wesolowski S, Bisgrove BW, Sunderland RT, Lin E, Lemmon G, Demarest BL, Miller TA, Bernstein D, Brueckner M, Chung WK, Gelb BD, Goldmuntz E, Newburger JW, Seidman CE, Shen Y, Yost HJ, Yandell M, Tristani-Firouzi M. De novo and recessive forms of congenital heart disease have distinct genetic and phenotypic landscapes Nature Communications 2019, 10: 4722. PMID: 31624253, PMCID: PMC6797711, DOI: 10.1038/s41467-019-12582-y.
- Histone H2B monoubiquitination regulates heart development via epigenetic control of cilia motilityRobson A, Makova SZ, Barish S, Zaidi S, Mehta S, Drozd J, Jin SC, Gelb BD, Seidman CE, Chung WK, Lifton RP, Khokha MK, Brueckner M. Histone H2B monoubiquitination regulates heart development via epigenetic control of cilia motility Proceedings Of The National Academy Of Sciences Of The United States Of America 2019, 116: 14049-14054. PMID: 31235600, PMCID: PMC6628794, DOI: 10.1073/pnas.1808341116.
- Genetic Basis for Congenital Heart Disease: Revisited: A Scientific Statement From the American Heart AssociationPierpont ME, Brueckner M, Chung WK, Garg V, Lacro RV, McGuire AL, Mital S, Priest JR, Pu WT, Roberts A, Ware SM, Gelb BD, Russell MW, Medicine O. Genetic Basis for Congenital Heart Disease: Revisited: A Scientific Statement From the American Heart Association Circulation 2018, 138: 1. PMID: 30571578, PMCID: PMC6555769, DOI: 10.1161/cir.0000000000000606.
- Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probandsJin SC, Homsy J, Zaidi S, Lu Q, Morton S, DePalma SR, Zeng X, Qi H, Chang W, Sierant MC, Hung WC, Haider S, Zhang J, Knight J, Bjornson RD, Castaldi C, Tikhonoa IR, Bilguvar K, Mane SM, Sanders SJ, Mital S, Russell MW, Gaynor JW, Deanfield J, Giardini A, Porter GA, Srivastava D, Lo CW, Shen Y, Watkins WS, Yandell M, Yost HJ, Tristani-Firouzi M, Newburger JW, Roberts AE, Kim R, Zhao H, Kaltman JR, Goldmuntz E, Chung WK, Seidman JG, Gelb BD, Seidman CE, Lifton RP, Brueckner M. Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands Nature Genetics 2017, 49: 1593-1601. PMID: 28991257, PMCID: PMC5675000, DOI: 10.1038/ng.3970.
- The NIMA-like kinase Nek2 is a key switch balancing cilia biogenesis and resorption in the development of left-right asymmetryEndicott S, Basu B, Khokha M, Brueckner M. The NIMA-like kinase Nek2 is a key switch balancing cilia biogenesis and resorption in the development of left-right asymmetry Journal Of Cell Science 2015, 128: e1.1-e1.1. DOI: 10.1242/jcs.184002.
- De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomaliesHomsy J, Zaidi S, Shen Y, Ware JS, Samocha KE, Karczewski KJ, DePalma SR, McKean D, Wakimoto H, Gorham J, Jin SC, Deanfield J, Giardini A, Porter GA, Kim R, Bilguvar K, López-Giráldez F, Tikhonova I, Mane S, Romano-Adesman A, Qi H, Vardarajan B, Ma L, Daly M, Roberts AE, Russell MW, Mital S, Newburger JW, Gaynor JW, Breitbart RE, Iossifov I, Ronemus M, Sanders SJ, Kaltman JR, Seidman JG, Brueckner M, Gelb BD, Goldmuntz E, Lifton RP, Seidman CE, Chung WK. De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies Science 2015, 350: 1262-1266. PMID: 26785492, PMCID: PMC4890146, DOI: 10.1126/science.aac9396.
- Intraciliary Calcium Oscillations Initiate Vertebrate Left-Right AsymmetryYuan S, Zhao L, Brueckner M, Sun Z. Intraciliary Calcium Oscillations Initiate Vertebrate Left-Right Asymmetry Current Biology 2015, 25: 556-567. PMID: 25660539, PMCID: PMC4469357, DOI: 10.1016/j.cub.2014.12.051.
- The NIMA-like kinase Nek2 is a key switch balancing cilia biogenesis and resorption in the development of left-right asymmetryEndicott SJ, Basu B, Khokha M, Brueckner M. The NIMA-like kinase Nek2 is a key switch balancing cilia biogenesis and resorption in the development of left-right asymmetry Development 2015, 142: 4068-4079. PMID: 26493400, PMCID: PMC4712839, DOI: 10.1242/dev.126953.
- De novo mutations in histone-modifying genes in congenital heart diseaseZaidi S, Choi M, Wakimoto H, Ma L, Jiang J, Overton JD, Romano-Adesman A, Bjornson RD, Breitbart RE, Brown KK, Carriero NJ, Cheung YH, Deanfield J, DePalma S, Fakhro KA, Glessner J, Hakonarson H, Italia MJ, Kaltman JR, Kaski J, Kim R, Kline JK, Lee T, Leipzig J, Lopez A, Mane SM, Mitchell LE, Newburger JW, Parfenov M, Pe’er I, Porter G, Roberts AE, Sachidanandam R, Sanders SJ, Seiden HS, State MW, Subramanian S, Tikhonova IR, Wang W, Warburton D, White PS, Williams IA, Zhao H, Seidman JG, Brueckner M, Chung WK, Gelb BD, Goldmuntz E, Seidman CE, Lifton RP. De novo mutations in histone-modifying genes in congenital heart disease Nature 2013, 498: 220-223. PMID: 23665959, PMCID: PMC3706629, DOI: 10.1038/nature12141.
- The Congenital Heart Disease Genetic Network StudyGelb B, Brueckner M, Chung W, Goldmuntz E, Kaltman J, Pablo Kaski J, Kim R, Kline J, Mercer-Rosa L, Porter G, Roberts A, Rosenberg E, Seiden H, Seidman C, Sleeper L, Tennstedt S, Kaltman J, Schramm C, Burns K, Pearson G, Rosenberg E, Newburger J, Breitbart R, Colan S, Geva J, Monafo A, Roberts A, Stryker J, Seidman C, McDonough B, Seidman J, Goldmuntz E, Edman S, Garbarini J, Hakonarson H, Mercer-Rosa L, Mitchell L, Tusi J, White P, Woyciechowski S, Chung W, Warburton D, Awad D, Celia K, Etwaru D, Sond J, Kline J, Korsin R, Lanz A, Marquez E, Williams I, Wilpers A, Yee R, Gelb B, Guevara D, Julian A, Mac Neal M, Mintz C, Peter I, Sachidanandam R, Seiden H, Romano-Adesman A, Gruber D, Stellato N, Brueckner M, Lifton R, Cross N, Deanfield J, Giardini A, Flack K, Porter G, Taillie E, Kim R, Tran N, Tennstedt S, Breitbart R, Dandreo K, Gallagher D, Lu M, Sleeper L, Berlin D, Beiswanger C, Lifton R, Seidman J, Hakonarson H, White P, Italia M, Chung W, Seidman C, Brooks (Chair) M, Olive M, Botkin J, Dupuis J, Garg V, Watson M, Bristow J, Evans T, Kendziorski C, Mardis E, Murray J, Saltz J, Wong H. The Congenital Heart Disease Genetic Network Study Circulation Research 2013, 112: 698-706. PMID: 23410879, PMCID: PMC3679175, DOI: 10.1161/circresaha.111.300297.
- Chapter 17 The Genetics of Fetal and Neonatal Cardiovascular DiseaseChung W, Boskovski M, Brueckner M, Anyane-Yeboa K, Gupta P. Chapter 17 The Genetics of Fetal and Neonatal Cardiovascular Disease 2012, 343-376. DOI: 10.1016/b978-1-4377-2763-0.00017-2.
- Cilia have Multiple Roles in the Development of the Vertebrate Left-Right AxisBrueckner M, McGrath J, Makova S. Cilia have Multiple Roles in the Development of the Vertebrate Left-Right Axis Microscopy And Microanalysis 2008, 14: 1480-1481. DOI: 10.1017/s1431927608085681.
- Monocilia in the embryonic mouse heart imply a direct role for cilia in cardiac morphogenesisBrueckner M, Slough J, Cooney L. Monocilia in the embryonic mouse heart imply a direct role for cilia in cardiac morphogenesis Developmental Biology 2008, 319: 602. DOI: 10.1016/j.ydbio.2008.05.436.
- Heterotaxia, Congenital Heart Disease, and Primary Ciliary DyskinesiaBrueckner M. Heterotaxia, Congenital Heart Disease, and Primary Ciliary Dyskinesia Circulation 2007, 115: 2793-2795. PMID: 17548739, DOI: 10.1161/circulationaha.107.699256.
- Two Populations of Node Monocilia Initiate Left-Right Asymmetry in the MouseMcGrath J, Somlo S, Makova S, Tian X, Brueckner M. Two Populations of Node Monocilia Initiate Left-Right Asymmetry in the Mouse Cell 2003, 114: 61-73. PMID: 12859898, DOI: 10.1016/s0092-8674(03)00511-7.
- Conserved function for embryonic nodal ciliaEssner JJ, Vogan KJ, Wagner MK, Tabin CJ, Yost HJ, Brueckner M. Conserved function for embryonic nodal cilia Nature 2002, 418: 37-38. PMID: 12097899, DOI: 10.1038/418037a.
- Cilia propel the embryo in the right directionBrueckner M. Cilia propel the embryo in the right direction American Journal Of Medical Genetics 2001, 101: 339-344. PMID: 11471157, DOI: 10.1002/1096-8628(20010715)101:4<339::aid-ajmg1442>3.0.co;2-p.
- Molecular motors: the driving force behind mammalian left–right developmentSupp D, Potter S, Brueckner M, Supp D, Potter S, Brueckner M. Molecular motors: the driving force behind mammalian left–right development Trends In Cell Biology 2000, 10: 41-45. PMID: 10652513, DOI: 10.1016/s0962-8924(99)01701-8.
- Of mice and men: Dissecting the genetic pathway that controls left‐right asymmetry in mice and humansSchneider H, Brueckner M. Of mice and men: Dissecting the genetic pathway that controls left‐right asymmetry in mice and humans American Journal Of Medical Genetics 2000, 97: 258-270. PMID: 11376437, DOI: 10.1002/1096-8628(200024)97:4<258::aid-ajmg1276>3.0.co;2-8.
- Targeted deletion of the ATP binding domain of left-right dynein confirms its role in specifying development of left-right asymmetriesSupp D, Brueckner M, Kuehn M, Witte D, Lowe L, McGrath J, Corrales J, Potter S. Targeted deletion of the ATP binding domain of left-right dynein confirms its role in specifying development of left-right asymmetries Development 1999, 126: 5495-5504. PMID: 10556073, PMCID: PMC1797880, DOI: 10.1242/dev.126.23.5495.
- GATA4 haploinsufficiency in patients with interstitial deletion of chromosome region 8p23.1 and congenital heart diseasePehlivan T, Pober B, Brueckner M, Garrett S, Slaugh R, Van Rheeden R, Wilson D, Watson M, Hing A. GATA4 haploinsufficiency in patients with interstitial deletion of chromosome region 8p23.1 and congenital heart disease American Journal Of Medical Genetics 1999, 83: 201-206. PMID: 10096597, DOI: 10.1002/(sici)1096-8628(19990319)83:3<201::aid-ajmg11>3.0.co;2-v.
- Handed asymmetry in the mouse: Understanding how things go right (or left) by studying how they go wrongSupp D, Brueckner M, Potter S. Handed asymmetry in the mouse: Understanding how things go right (or left) by studying how they go wrong Seminars In Cell And Developmental Biology 1998, 9: 77-87. PMID: 9572117, DOI: 10.1006/scdb.1997.0186.
- Mutation of an axonemal dynein affects left–right asymmetry in inversus viscerum miceSupp D, Witte D, Potter S, Brueckner M. Mutation of an axonemal dynein affects left–right asymmetry in inversus viscerum mice Nature 1997, 389: 963-966. PMID: 9353118, PMCID: PMC1800588, DOI: 10.1038/40140.
- The genetics of left-right development and heterotaxiaBowers P, Brueckner M, Yost H. The genetics of left-right development and heterotaxia Seminars In Perinatology 1996, 20: 577-588. PMID: 9090782, DOI: 10.1016/s0146-0005(96)80070-x.
- Laterality disturbancesBowers P, Brueckner M, Yost H. Laterality disturbances Progress In Pediatric Cardiology 1996, 6: 53-62. DOI: 10.1016/1058-9813(96)00171-3.
- ANALYSIS OF A CANDIDATE MOUSE IV (INVERSUS VISCERUM) GENE. • 123Bowers P, Yoon J, Horwich A, Brueckner M. ANALYSIS OF A CANDIDATE MOUSE IV (INVERSUS VISCERUM) GENE. • 123 Pediatric Research 1996, 39: 23-23. DOI: 10.1203/00006450-199604001-00142.
- Isolation of murine telomere-proximal sequences by affinity capture and PCR.Rounds D, Brueckner M, Ward DC. Isolation of murine telomere-proximal sequences by affinity capture and PCR. Genomics 1995, 29: 616-22. PMID: 8575753, DOI: 10.1006/geno.1995.9958.
- Left, right and without a cueHowrich A, Brueckner M. Left, right and without a cue Nature Genetics 1993, 5: 321-322. PMID: 8298636, DOI: 10.1038/ng1293-321.
- Intestinal rotation and fixation abnormalities in heterotaxia: early detection and management.Chang J, Brueckner M, Touloukian RJ. Intestinal rotation and fixation abnormalities in heterotaxia: early detection and management. Journal Of Pediatric Surgery 1993, 28: 1281-4; discussion 1285. PMID: 8263687, DOI: 10.1016/s0022-3468(05)80313-6.
- Genetic aspects of heart disease in the newborn.Bulbul ZR, Rosenthal D, Brueckner M. Genetic aspects of heart disease in the newborn. Seminars In Perinatology 1993, 17: 61-75. PMID: 8327904.
- Neonatal correction of transposition of the great arteries: the Connecticut experience.Dewar ML, Kleinman C, Hellenbrand W, Fahey J, Talner N, Brueckner M, Kopf GS. Neonatal correction of transposition of the great arteries: the Connecticut experience. Connecticut Medicine 1992, 56: 671-4. PMID: 1288934.
- Duplication/deficiency mapping of situs inversus viscerum (iv), a gene that determines left-right asymmetry in the mouseMcGrath J, Horwich A, Brueckner M. Duplication/deficiency mapping of situs inversus viscerum (iv), a gene that determines left-right asymmetry in the mouse Genomics 1992, 14: 643-648. PMID: 1427890, DOI: 10.1016/s0888-7543(05)80163-6.
- Establishment of Left‐Right Asymmetry in Vertebrates: Genetically Distinct Steps are InvolvedBrueckner M, McGrath J, D'Eustachio P, Horwich A. Establishment of Left‐Right Asymmetry in Vertebrates: Genetically Distinct Steps are Involved 1991, 162: 202-218. PMID: 1802643, DOI: 10.1002/9780470514160.ch12.
- Linkage mapping of a mouse gene, iv, that controls left-right asymmetry of the heart and viscera.Brueckner M, D'Eustachio P, Horwich AL. Linkage mapping of a mouse gene, iv, that controls left-right asymmetry of the heart and viscera. Proceedings Of The National Academy Of Sciences Of The United States Of America 1989, 86: 5035-5038. PMID: 2740340, PMCID: PMC297551, DOI: 10.1073/pnas.86.13.5035.
- Linkage mapping of a mouse gene, iv, that controls left-right asymmetry of the heart and visceraBrueckner M, D'Eustachio P, Horwich A. Linkage mapping of a mouse gene, iv, that controls left-right asymmetry of the heart and viscera Trends In Genetics 1989, 5: 324. DOI: 10.1016/0168-9525(89)90134-0.
Clinical Trials
Conditions | Study Title |
---|---|
Diseases of the Cardiovascular System | Genomic Basis of Neurodevelopmental and Brain Outcomes in Congenital Heart Disease (CHD Brain and Genes) |
Diseases of the Cardiovascular System; Genetics - Adult; Genetics - Pediatric | Congenital Heart Disease GEnetic NEtwork Study (CHD GENES) |