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Martina Brueckner, MD

Professor of Pediatrics (Cardiology)
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Pediatric Cardiology

PO Box 208064

New Haven, CT 06520-8064

United States

About

Titles

Professor of Pediatrics (Cardiology)

Biography

Martina Brueckner obtained her BS and MD degrees from the University of Virginia, followed by a Pediatric Residency at the University of Pittsburgh and a Pediatric Cardiology Fellowship at Yale University School of Medicine. Her clinical and research focus is genetics of congenital heart disease (CHD). The goal of the lab's work is to determine the genetic cause and developmental mechanisms underlying CHD with a focus on the function of cilia in heart development. Our work 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, identifying genes and mechanism by which motile and immotile cilia establish 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 genomic approaches to a more comprehensive understanding of human CHD. We are focusing on the ability to identify the genetic causes of CHD, and to directly test putative genetic causes of human CHD identified from genomic analysis of patient DNA in animal model systems including mouse and zebrafish, and finally to link genetic and developmental mechanisms of CHD to improved care of patients with CHD.

Dr. Brueckner's clinical focus is on patients with genetic causes of congenital heart disease. It has become increasingly apparent that a large portion of cardiovascular disease in children and adolescents has as its underlying etiology a genetic defect. Dr. Brueckner co-founded one of the first pediatric cardiac genetics clinics at Yale-New Haven Children's Hospital. The clinic provides comprehensive diagnostic evaluation and follow-up care for patients with genetic-cardiovascular disease. Dr. Brueckner has been a staff cardiologist since completing her fellowship at Yale in 1990.

Appointments

Education & Training

Fellow
Yale University School of Medicine (1990)
Resident
University of Pittsburgh Children's Hospital (1987)
Intern
University of Pittsburgh, School of Medicine (1985)
MD
University of Virginia (1984)

Research

Overview

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.

Medical Subject Headings (MeSH)

Cardiology; Genetics; Heart Diseases; Heterotaxy Syndrome; Kartagener Syndrome; Situs Inversus

Research at a Glance

Yale Co-Authors

Frequent collaborators of Martina Brueckner's published research.

Publications

2023

2022

Clinical Trials

Current Trials

Academic Achievements & Community Involvement

  • activity

    Medical School Admissions Committee

  • activity

    NIH

  • activity

    American Heart Association Founders Affiliate Research Committee

  • honor

    Member

  • honor

    Member

Clinical Care

Overview

Martina Brueckner, MD, is a pediatric cardiologist who integrates the latest findings in the genetic causes of congenital heart disease into her patient care. She says Yale Medicine provides a unique genetics-cardiology clinic that combines care for patients with congenital heart disease with state-of-the-art genetic testing and counseling. She tells new parents, “You did not cause your child's heart disease. Most people with congenital heart disease today survive.”

A professor of pediatrics (cardiology) at Yale School of Medicine, Dr. Brueckner is also an active researcher seeking to expand knowledge of the genomic underpinnings of congenital heart disease. “The goal of my work is to determine the genetic cause and developmental mechanisms underlying congenital heart disease, and to use those discoveries to improve care,” she says.

Dr. Brueckner is excited by significant advances in the understanding of congenital heart disease genetics, and she believes they will eventually allow doctors to optimize outcomes by tailoring care to each individual patient. “I am certain that we can dramatically improve the quality of life for people with congenital heart disease through research focused on the basic underlying causes,” she says.

Clinical Specialties

Pediatrics; Pediatric Cardiology; Pediatric Genetics

Fact Sheets

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Contacts

Appointment Number
Office Fax Number
Clinic Fax Number
Mailing Address

Pediatric Cardiology

PO Box 208064

New Haven, CT 06520-8064

United States

Locations

  • Fitkin Memorial Pavilion

    Academic Office

    789 Howard Avenue, Wing Fitkin, Fl 4, Ste 426

    New Haven, CT 06519

  • Fitkin Memorial Pavilion

    Lab

    789 Howard Avenue, Wing Fitkin, Fl 4, Ste 426

    New Haven, CT 06519

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