The Norris lab has over 25 years of experience understanding genetics of syndromic
and non-syndromic diseases like mitral valve prolapse (MVP), aortic stenosis, bicuspid aortic valve diseases, and cardiomyopathies. Our current areas of research include mitral valve prolapse, myocardial fibrosis, and cardivascular development.
Mutations in DCHS1 cause mitral valve prolapse
Mitral Valve Prolapse
Mitral valve prolapse (MVP) affects 2% to 3% of the general population and is associated with secondary co‐morbidities such as arrhythmias, heart failure, and sudden cardiac death. MVP is characterized as the billowing of one or both leaflets above the level of the mitral annulus during cardiac systole. Structural changes of the valve result in an inability for the valve to be mechanically proficient during the cardiac cycle. These changes are characterized by alterations in the amount and types of extracellular matrix (ECM) present within the valves. Over time, the valve becomes thickened and floppy which results in incompetence, prolapse, and mitral regurgitation. Surgery is the only curative option for patients with severe MVP.
Familial studies by the Norris lab and others have demonstrated that MVP can manifest during childhood, suggesting that genetic abnormalities expressed during valve development become exacerbated over a lifetime. Causes of MVP remain poorly understood. However, we recently reported data from two approaches that have made significant inroads into understanding the genetics and etiology of MVP.
First, we identified loss of function mutations in the cell polarity gene, DCHS1 in three families with inherited MVP. Additionally genetic studies identified mutations in another gene, DZIP1 as segregating with MVP in multiple families.
Pathway analyses of genome wide variants combined with the discovery of DCHS1 and DZIP1 mutations led to the hypothesis that primary cilia are a unifying pathway regulating mitral valve structure and function. Primary cilia are solitary cellular protrusions that function as “antennae”. Our finding that primary cilia are primarily observed during development further supported the new paradigm that MVP is a developmentally based disease that progressively gets worse with age.
Myocardial fibrosis has been identified in one in three mitral valve prolapse patients and is associated with an increased risk of life threatening ventricular arrhythmias and sudden cardiac death. Current surgical guidelines do not assess for myocardial fibrosis and may be unable to risk stratify patients who may develop ventricular arrhythmias. Furthermore, mechanisms that link mitral valve prolapse to myocardial fibrosis are not well defined.
The Norris lab was one of the first to show that myocardial fibrosis is caused by increases in biomechanical stress caused by a prolapsing mitral valve leaflet. We have further identified changes in kinase activity, epigenetic cell state, and transcription that may define how cells respond to mechanical stress. Collectively, our goal is to build a mechano-molecular landscape that allows us to link mechanical stress to precise biological pathways that drive fibrosis, identify new molecular targets to treat myocardial fibrosis, and demonstrate that traditional surgical guidelines need to be modified to allow for identification of high risk arrhythmic MVP patients who may need earlier surgery.
In previous studies from the Norris laboratory, a gene was found and investigated for its role in mitral valve prolapse and an observed myxomatous valve phenotype. Interestingly, homologous genetic knockout mice were found to be neonatally lethal and exhibit strange heart morphology. This has lead our lab to investigate the regulatory pathways in these neonatal mice and cell-to-cell interactions in the developing heart. In particular, we are focused on protein expression and interactions within and between fibroblasts and cardiomyocytes and their effect on cell proliferation and maturation. We are in the process of analyzing single-cell RNA sequencing data as well as performing further molecular studies on these mice to determine the pathophysiology. Out ultimate goal is to elucidate some of the mechanisms behind heart maturation and development.
Acute Rheumatic Fever Biomarker Project
In association with the LeDucq Foundation and LeDucq Prima Network
Acute rheumatic fever (ARF) causing rheumatic heart disease (RHD) remains a cause of heart failure, stroke and maternal mortality in many developing countries. ARF is a potential complication of an untreated strep throat infection in which the immune response turns against the host. Most patients with RHD lack a known early diagnosis of ARF, losing opportunities to prevent crippling heart damage from recurrent strep infections through antibiotic prophylaxis. Our network aims to find an early circulating marker of ARF by an interdisciplinary team of physicians and scientists using cutting-edge technologies and complementary approaches:
1) Community outreach and education championed by groups in areas with frequent ARF in Brazil, India, Tanzania and Uganda will aim to find children and adolescents who can benefit most to prevent damage but are now largely missed at an early stage.
2) Biomarker discovery will be not only by protein-wide analysis but also maximized based on the science of how the underlying strep bacterial infection generates an immune attack on the heart and other organs. This approach will draw on network strengths and synergies of investigators who have determined the key molecular triggers of this immune attack and will study how immune cells from patients with ARF respond to those triggers. Network synergies will enable results not achievable by individual groups alone.
3) Results will be translated to practical point-of-care testing by members with this expertise.
4) The network builds on active collaborations and, in preliminary studies for this purpose, has discovered novel RHD biomarkers in shared specimens to be tested in ARF. While recruiting patients with early ARF, it is poised to begin work on existing RHD sample collections with a centralized biorepository. Network meetings will interface with government and health agencies to support ARF infrastructure and recruitment. The network will advance investigators in endemic regions and create new scientific knowledge and clinical resources not only to guide current prevention but also to enable vaccine development and testing of novel therapeutics.