Variants to Function & Mechanism

Variants to Function & Mechanism2024-07-02T14:12:09-04:00

Determining the detailed mechanisms by which variants in the human genome or genes associated with human genetic variants operate to contribute to disease or health/wellness.

News | Variants to Function & Mechanism

Huntingtin turnover: modulation of huntingtin degradation by cAMP-dependent protein kinase A (PKA) phosphorylation of C-HEAT domain Ser2550

Huntington’s disease (HD) is a neurodegenerative disorder caused by an inherited unstable HTT CAG repeat that expands further, thereby eliciting a disease process that may be initiated by polyglutamine-expanded huntingtin or a short polyglutamine-product. Phosphorylation of selected candidate residues is reported to mediate polyglutamine-fragment degradation and toxicity. In this manuscript, CGM Investigators Ihn Sik Seong, Marcy MacDonald and colleagues used deep mass spectrometry-based phosphoproteomics to systematically identify sites in purified huntingtin and in the endogenous protein. The analyses identified as many as 95 total phospho-sites in Huntingtin, including phosphorylation of C-HEAT Ser2550 by AMP-dependent protein kinase (PKA), which was found to hasten huntingtin degradation. This work highlights categories of phosphosites and biological processes that regulate huntingtin degradation that are relevant to HD pathogenesis and merit further study.

June 21, 2023

Publication

CGM Primary Investigator

June 21, 2023|

Long-term effects of l-serine supplementation upon a mouse model of diabetic neuropathy

Deoxysphingolipids (1-deoxySLs) are neurotoxic sphingolipids associated with obesity and diabetic neuropathy (DN) and have been linked to severity of functional peripheral neuropathies. L-serine supplementation can reduce 1-deoxySL accumulation and improve insulin sensitivity and sensory nerve velocity, but long-term outcomes have not yet been examined. In this work published by CGM investigator Florian Eichler and colleagues, a preclinical model of diabetic neuropathy was treated oral l-serine and longitudinally quantified the extent of functional neuropathy progression. Functional neuropathy and sensory modalities were significantly improved in the treatment group well into advanced stages of disease, however, structural assessments revealed prominent axonal degeneration, apoptosis and Schwann cell pathology, suggesting that neuropathy was ongoing. Thus, despite significant functional improvements, L-serine does not prevent chronic degenerative changes specifically at the structural level, pointing to other processes such as oxidative damage and hyperglycemia that may have additional pathological effects in DN.

June 21, 2023

Publication

CGM Primary Investigator

June 21, 2023|

Heterozygous mutations in SOX2 may cause idiopathic hypogonadotropic hypogonadism via dominant-negative mechanisms

Pathogenic SRY-box transcription factor 2 (SOX2) variants typically cause severe ocular defects within a SOX2 disorder spectrum that includes hypogonadotropic hypogonadism. In this work published by CGM associate member Ravi Balasubramanian, CGM senior associate member Stephanie Seminara, and CGM investigator Bill Crowley, exome-sequencing data from a large, well-phenotyped cohort of patients with idiopathic hypogonadotropic hypogonadism (IHH) was mined for pathogenic SOX2 variants. They identified 8 IHH individuals harboring heterozygous pathogenic SOX2 variants with variable ocular phenotypes, going on to determine that Sox2 is highly expressed in the hypothalamus of adult mice and colocalized with kisspeptin 1 (KISS1) expression, and suppression of mouse SOX2 protein increased the levels of human kisspeptin, which has previously been invoked in IHH. These data suggest that pathogenic SOX2 variants contribute to both anosmic and normosmic forms of IHH, and highlights the necessity of SOX2 screening in IHH genetic evaluation irrespective of associated ocular defects.

Read more in JCI Insight.

June 21, 2023

Publication

CGM Primary Investigators

Stephanie Seminara

Bill Crowley

June 21, 2023|

Proteasomal pathway inhibition as a potential therapy for NF2-associated meningioma and schwannoma

Neurofibromatosis 2 (NF2) is an inherited disorder caused by bi-allelic inactivation of the NF2 tumor suppressor gene. NF2-associated tumors, including schwannoma and meningioma, are resistant to chemotherapy, often recurring despite surgery and/or radiation, and have generally shown cytostatic response to signal transduction pathway inhibitors, highlighting the need for improved cytotoxic therapies. In this manuscript by CGM investigator Vijaya Ramesh and colleagues, data from previous high-throughput drug screening in NF2 preclinical models was leveraged to identify a class of compounds targeting the ubiquitin-proteasome pathway (UPP) that may have utility in NF2. Through a series of elaborate investigation of these UPP targeting agents in vitro and in vivo, the group found that treatment delayed tumor growth, suggesting a therapeutic potential. This important work in preclinical models lays the groundwork for use of these drugs as a promising novel treatment strategy for NF2 patients.

Read more in Neuro-Oncology

June 21, 2023

Publication

CGM Primary Investigator

June 21, 2023|

CHIPping away at cardiovascular disease

Clonal hematopoiesis of indeterminate potential (CHIP), a condition defined by a set of aging-related genetic mutations in blood cells, is associated with an increased risk of several conditions. A team led by CGM PI Pradeep Natarajan and colleagues from Centro Nacional de Investigaciones Cardiovasculares, Stanford University, and Vanderbilt University explored the relationship between CHIP and atherosclerosis in the peripheral arteries. Individuals with mutations in DNA damage repair genes had an increased risk, and mouse data indicated that such mutations may drive increased aortic plaque size and accumulation of macrophages within plaques.

June 21, 2023

Publication

CGM Primary Investigator

June 21, 2023|

Development of an oral treatment that rescues gait ataxia and retinal degeneration in a phenotypic mouse model of familial dysautonomia.

Familial dysautonomia (FD) is a rare neurodegenerative disease caused by a mutation in the gene encoding for the Elongator complex protein 1 (ELP1). This mutation leads to a reduction of ELP1 protein, mainly in the nervous system. Due to the crucial function of ELP1 in neuronal development and survival, FD patients exhibit many neurological symptoms, including retinal degeneration and inability to coordinate movements. In our recently published study, the Slaugenhaupt and Morini lab describes the optimization of an oral treatment for FD that restores the expression of functional ELP1 protein in every tissue, including brain, and rescues retinal degeneration and motor coordination in a mouse model of FD.

March 20, 2023

Publication

CGM Primary Investigators

Sue Slaugenhaupt

Elisabetta Morini

March 20, 2023|

Faculty | Variants to Function & Mechanism

Rakesh Karmacharya, MD, PhD

Categories: Training Program Faculty, Variants to Disease & Traits, Variants to Function & Mechanism
Harvard Medical School: Associate Professor of Psychiatry
Massachusetts General Hospital: Physician Investigator
Physician Investigator, Massachusetts General Hospital
Associate Professor, Harvard Medical School

Our lab uses experimental approaches at the intersection of chemical biology, genetics and stem cell biology to investigate cellular pathways relevant to schizophrenia, bipolar disorder, autism and related neuropsychiatric disorders. We utilize complementary approaches in specific cellular subtypes and in three-dimensional cerebral organoids generated from human iPSCs. We employ a range of methods including high-content imaging to investigate synaptic biology, multi-electrode arrays to examine neuronal function along with transcriptomic, proteomic and metabolomic experiments. We seek to develop new small molecules that can modulate disease-related processes in patient-derived neurons and develop new therapeutic approaches for targeting cognitive deficits in psychiatric disorders.

Rakesh Karmacharya, MD, PhD

Associate Professor of Psychiatry, Harvard Medical School

W. Taylor Kimberly, MD, PhD

Categories: Variants to Disease & Traits, Variants to Function & Mechanism
Harvard Medical School: Associate Professor of Neurology
Massachusetts General Hospital: Chief, Division of Neurocritical Care
Chief, Division of Neurocritical Care, Massachusetts General Hospital
Associate Professor of Neurology, Harvard Medical School

The Kimberly Lab is committed to reducing the devastating effects of acute brain injury by focusing on translational studies that bridge basic science and clinical research. We believe that therapeutic discovery is not a linear path from fundamental mechanism to new drug, but instead a cycle that requires bi-directional and multidisciplinary integration of basic and patient-oriented research. A presence at each stage of discovery—both directly and through strategic collaboration—is central to our mission to advancing new treatments. Consequently, our laboratory is highly multidisciplinary and collaborative, and our work could not be accomplished without our collaborative partners.

W. Taylor Kimberly, MD, PhD

Associate Professor of Neurology, Harvard Medical School

Ben P. Kleinstiver, PhD

Categories: Variants to Disease & Traits, Variants to Function & Mechanism
Harvard Medical School: Assistant Professor of Pathology
Massachusetts General Hospital: Investigator; Kayden-Lambert MGH Research Scholar 2023-2028
Investigator; Kayden-Lambert MGH Research Scholar 2023-2028, Massachusetts General Hospital
Assistant Professor, Harvard Medical School

The Kleinstiver lab develops genome editing technologies for research applications and for the treatment of human diseases. We develop new approaches and methods to engineer genome editing enzymes, to optimize the properties of CRISPR tools, and to add new functionalities to the editor toolbox, all with the ambition of enabling new treatments for disease.

Ben P. Kleinstiver, PhD

Assistant Professor of Pathology, Harvard Medical School

Phil H. Lee, PhD

Categories: Variants to Diagnosis, Variants to Disease & Traits, Variants to Function & Mechanism
Harvard Medical School: Assistant Professor of Psychiatry
Massachusetts General Hospital: Assistant in Research
Assistant in Research, Massachusetts General Hospital
Assistant Professor, Harvard Medical School

We use computational and statistical approaches to understand the genetic bases of complex neuropsychiatric traits and mental disorders. Multivariate pathway analysis forms the backbone of our research on identifying disease risk genes and mechanisms. We also apply multi-modal data analysis integrating genomic and neuroimaging data.

Phil H. Lee, PhD

Assistant Professor of Psychiatry, Harvard Medical School

Marcy E. MacDonald, PhD

Categories: Populations to Variants, Variants to Diagnosis, Variants to Disease & Traits, Variants to Function & Mechanism
Harvard Medical School: Professor of Neurology
Massachusetts General Hospital: Research (Non-Clinical) Staff
Research (Non-Clinical) Staff, Massachusetts General Hospital
Professor of Neurology, Harvard Medical School

Our research, evolving from the discovery of the genetic causes of inherited brain disorders (hereditary spastic paraparesis, neurofibromatosis, neuronal ceroid lipofuscinosis, Huntington’s disease), is now largely focused on the DNA variants that modify the effects of the unstable expanded CAG repeat that causes Huntington’s disease. We do molecular genetic studies with disease and population cohorts and genetically precise model systems. Our goal is to enable timely intervention, diagnosis and disease-management.

Marcy E. MacDonald, PhD

Professor of Neurology, Harvard Medical School

Jonathan Rosand, MD, MSc

Categories: Training Program Faculty, Variants to Disease & Traits, Variants to Function & Mechanism
Harvard Medical School: Professor of Neurology
Massachusetts General Hospital: J. P. Kistler Endowed Chair in Neurology
J. P. Kistler Endowed Chair in Neurology, Massachusetts General Hospital
Professor of Neurology, Harvard Medical School

The hallmark of our work is the combination of careful clinical characterization of patients with the most rigorous approaches to genetics. We work in partnership with patients and their families to understand the factors that contribute to maintaining vascular brain health across the lifespan. We are a leading contributor to the performance and analysis of high-throughput genome-wide association and sequencing studies in stroke and related traits. At our core, we serve as a training ground for outstanding scientists and clinician-scientists who go on to become world-class leaders in the field. The lab has created a legacy of multidisciplinary teams that are successfully tackling some of the most pressing challenges in brain disease. Among these teams is the International Stroke Genetics Consortium, which we founded in 2007 to bring together the world’s pre-eminent stroke investigators.

Jonathan Rosand, MD, MSc

Professor of Neurology, Harvard Medical School

Jeremiah M. Scharf, MD, PhD

Categories: Populations to Variants, Training Program Faculty, Variants to Diagnosis, Variants to Disease & Traits, Variants to Function & Mechanism
Harvard Medical School: Assistant Professor of Neurology
Massachusetts General Hospital: Physician-Scientist
Physician-Scientist, Massachusetts General Hospital
Assistant Professor of Neurology, Harvard Medical School

The Scharf lab investigates the genetic and neurobiological mechanisms of Tourette Syndrome (TS) and related developmental neuropsychiatric disorders that lie at the interface between traditional concepts of neurologic and psychiatric disease, including obsessive compulsive spectrum disorders (OCD/OCSD) and attention-deficit hyperactivity disorder (ADHD). We conduct genetic and clinical research to identify both genetic and non-genetic risk factors that contribute to the predisposition of TS, ADHD, and OCD in patients and families. We hope to identify novel targets for treatment, to understand the course of TS and related conditions at a patient-specific level, and to better predict treatment response.

Jeremiah M. Scharf, MD, PhD

Assistant Professor of Neurology, Harvard Medical School

Jordan W. Smoller, MD, ScD

Categories: Training Program Faculty, Variants to Diagnosis, Variants to Disease & Traits, Variants to Function & Mechanism
Harvard Medical School: Professor of Psychiatry
Massachusetts General Hospital: MGH Trustees Endowed Chair in Psychiatric Neuroscience
Massachusetts General Hospital: MGH Trustees Endowed Chair in Psychiatric Neuroscience
MGH Trustees Endowed Chair in Psychiatric Neuroscience, Massachusetts General Hospital
MGH Trustees Endowed Chair in Psychiatric Neuroscience, Massachusetts General Hospital
Professor of Psychiatry, Harvard Medical School

The focus of Dr. Smoller’s research interests has been:

  • Understanding the genetic and environmental determinants of psychiatric disorders across the lifespan.
  • Integrating genomics and neuroscience to unravel how genes affect brain structure and function.
  • Using “big data”, including electronic health records and genomics, to advance precision medicine.

Jordan W. Smoller, MD, ScD

Professor of Psychiatry, Harvard Medical School

We are hiring! We are inviting applications for full-time CGM faculty with an Assistant or Associate Professor of Neurology appointment at Harvard Medical School (HMS), commensurate with accomplishments and experiences. See more and apply on our careers page >

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