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Research in Genetics |
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The General Genetics Program works closely with the Genetics Division's research laboratories, headed by Dr. Louis Kunkel. These laboratories are devoted to the study of genes that underlie inherited disorders and the function of their encoded proteins. This relationship between the General Genetics Program and the laboratories facilitates the rapid transition of progress in the laboratory to clinical applications.
The research program of the Division has been very productive, starting with the early cytogenetic work of Drs. Park S. Gerald and Samuel A. Latt, followed by the landmark somatic cell hybrid work of Dr. Gail Bruns and the specific phage libraries of Dr. Latt. Both of these efforts were part of the foundations of the Human Genome Project and led to the later positional cloning success of the Division. These successes included isolating the gene for Duchenne Muscular Dystrophy, Aniridia/Wilms Tumor, two forms of Limb Girdle Muscular Dystrophy, Angelman syndrome, and a form of Nemaline Myopathy, just to name a few.
Recent work has centered on the genetics of extreme longevity (Dr. Kunkel), the pathogenesis of muscular dystrophies and myoptathies (Drs. Beggs and Kunkel), stem cell therapy of genetic diseases (Drs. Gussoni and Kunkel), cranial nerve involvement in eye muscle disorders (Dr. Engel), ancient conserved sequence motifs (Dr. Bruns) and disorders of cholesterol metabolism (Dr. Irons).
More information on our researchers and their research studies can be found below.
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Alan Beggs, PhD
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Genetics of neuromuscular disease
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Gail Bruns, MD, PhD
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WAGR Syndrome
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Elizabeth Engle, MD
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Congenital eye movement disorders
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Emanuela Gussoni, PhD
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Muscular dystrophy
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Joel Hirschhorn, MD, PhD
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Endocrine genetics
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Ingrid Holm, MD, MPH
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Endocrine genetics
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Mira Irons, MD
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Smith-Lemli-Opitz syndrome; Neurofibromatosis Type1
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Louis Kunkel, PhD
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Muscular dystrophy
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Harvey Levy, MD
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Biochemical disorders; Phenylketonuria (PKU)
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Jonathan Picker, MBChB, MSC, PhD
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Neurobiology of behavioral disorders; Fragile X syndrome
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Christopher Walsh, MD
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Development and function of the human cerebral cortex
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Alan Beggs' research is aimed at understanding the structures and function of the proteins that make up skeletal muscle fibers. Beggs and colleagues are taking two approaches to the problem. The first involves identifying and characterizing new skeletal muscle genes and proteins. The second entails identifying genetic mutations that cause human neuromuscular disease. These simultaneous approaches should enable them to correlate their basic muscle biology findings with their studies on muscle tissue in patients with neuromuscular diseases.
The diseases under study include nemaline myopathy, myotubular myopathy, congenital fiber type disproportion, multiminicore disease, and congenital myopathies with non-specific muscle findings.
The Beggs Laboratory
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Gail Bruns' research is focused on genes and chromosomal regions associated with human developmental anomaly disorders. She is particularly interested in the region of chromosome 11 that is deleted in the WAGR syndrome (Wilms tumor, aniridia, genitourinary anomalies, and mental retardation). The genes in this region are important for normal development of the eye, brain, kidney, and genitourinary system. The region also contains one of the genes for Wilms tumor.
Her laboratory has isolated a novel gene from a subregion of the deleted area that is implicated in at least part of the mental retardation component of the syndrome. It is predominantly expressed in the developing forebrain. This gene is the index member of a new family of neural genes that are homologous to those in the nematode (C. elegans) genome - an indication that they serve, or once served, a vital function. Bruns and her co-workers are also mapping the human genes that are homologous to genes that play key roles in developmental processes in the nematode, drosophila, zebrafish, and mouse.
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Elizabeth Engle's research focuses on uncovering the genetic causes of common and complex strabismus. In particular, the lab's primary goal has been to understand the molecular basis of a group of pediatric eye movement disorders referred to as the congenital cranial dysinnervation disorders (CCDDs). To that end, research projects in the Engle laboratory include family studies to locate and identify the genes mutated in the various forms of these disorders. Once a gene is identified, they study its normal and abnormal protein product to determine the role of the gene in health and disease.
The Engle lab has established that the CCDDs result from errors in the development of cranial neurons and their axons in the brainstem and orbit. It has identified the causes for CFEOM2, Duane syndrome with radial anomalies, CFEOM1, horizontal gaze palsy with progressive scoliosis, and BSAS and ABSD syndromes.
The Engle Laboratory
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The Gussoni laboratory's long-term goal is to optimize a cell-based therapy for patients with muscular dystrophy. Dr. Gussoni and colleagues are now pursuing this goal by optimizing human muscle stem cell isolation and characterization, as well as by creating new animal models for preclinical testing. They also are thoroughly comparing the transcriptome - the set of active genes - of human muscle stem cells to that of committed muscle cells using microarray technology. These studies are expected to lead to the identification of specific muscle stem cell markers that will make it easier to purify stem cells from primary tissues.
Down the road, the group seeks to identify the mechanisms by which muscle stem cells fuse to pre-existing myofibers and to optimize the injection of human muscle stem cells in immunocompromised mice with muscular dystrophy.
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The Hirschhorn laboratory's long-term goal is to understand the genetic basis of complex traits, such as obesity and diabetes. In particular, the laboratory identifies DNA sequence variants (usually SNPs) located in genes or chromosomal regions of interest, and genotype these in large, well-characterized samples. The analysis ranges from simple comparisons of the frequencies of the variants in healthy individuals and patients with disease to more complex haplotype-based analyses and analyses of quantitative traits.
Currently, the researchers' main emphasis is on obesity and stature. They are taking both a candidate gene and positional cloning approach to finding obesity genes and are attempting to positionally clone at least one quantitative trait locus (QTL) for stature.
Hirschhorn and colleagues are also studying breast cancer and type 2 diabetes in an ongoing collaboration with David Altshuler. Because they can generate data rapidly, investigators in the lab will be able to ask and answer such questions as, "Does common genetic variation in hormones that regulate appetite contribute to human obesity?"
The Hirschhorn team is also working on a population genetics project designed to identify regions of the genome that have undergone strong recent positive selection, and have described a strong signal surrounding the lactase gene. Finally, they continue to strive to develop analytic and laboratory methods to facilitate genetic studies of complex traits.
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Ingrid Holm's research focuses on the genetics of bone disorders. She has performed research in the role of mutations in the PHEX gene in hypophosphatemic rickets. Her studies have sought to elucidate the genetic and environmental components of disorders of bone mineralization. She is particularly interested in the contribution of environmental factors to the low bone mass seen in individuals with neuromuscular diseases, such as muscular dystrophy.
Dr. Holm is interested in the genetics of complex traits. As director of the Phenotype Core of the Program in Genomics, she has worked with researchers to develop clinical genetic research projects in diabetes, autism, congenital heart disease, and atopic dermatitis, and has her own project in the genetic contributions to congenital hip dysplasia.
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Since 1993, the main focus of Dr. Irons' research activities has been studying the cholesterol biosynthetic defect in patients with Smith-Lemli-Opitz syndrome. Since discovering this new inborn error of metabolism, Dr. Irons has developed a treatment protocol for treating affected patients with cholesterol supplementation that has led to improvements in growth and psychomotor development and is now considered standard therapy for this condition. Additionally, Dr. Irons led the team that participated in the first prenatal treatment for this disorder, and has continued to study the effects of cholesterol deficiency and response to cholesterol supplementation on numerous organ systems in affected patients with her collaborators. She has also studied genotype-phenotype correlations in these patients.
More recently, Dr. Irons has begun to investigate altered cholesterol metabolism in children with developmental delays or mental retardation who do not have Smith-Lemli-Opitz syndrome to determine whether deficiency of cholesterol contributes to developmental disability and may be amenable to therapy.
Dr. Irons has several additional research interests, including the study of aberrations of growth and pubertal development in children with Neurofibromatosis, Type 1 (NF1). The Children's Hospital Neurofibromatosis Program under her leadership has recently been chosen by the Department of Defense to form a clinical trials consortium with 8 other Neurofibromatosis centers in the United States. This group of NF centers will join together to develop and implement clinical trials in NF1 for treatment of complications of this condition, including neurofibomas, optic gliomas, and learning disabilities.
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Louis Kunkel has years of experience and scientific success in the understanding of the basis for muscular dystrophies. Over the past three decades, Dr. Kunkel has devoted his career to understanding the molecular basis, and developing therapy, for neuromuscular disorders. Dr. Kunkel is universally recognized for the identification of the gene and encoded protein, dystrophin, which is altered in boys with Duchenne/Becker muscular dystrophy.
In the years after the discovery of dystrophin, members of his laboratory have been responsible for the identification and characterization of more than 15 dystrophin-related or dystrophin-associated genes and their protein products, and have discovered that mutations in three of these genes cause limb-girdle muscular dystrophy. Kunkel's work has led to improved diagnosis of the muscular dystrophies, a new understanding of the common pathogenesis underlying these disorders, and testable ideas on therapeutic intervention. The latter effort is now one of the main focuses of his lab.
The Kunkel lab is working on a method to introduce the deficient protein into the dystrophic muscle. The replacement of absent dystrophin in dystrophic mice by transgenic expression leads to complete restoration of normal muscle cell membrane function. Human clinical trials of intra-muscular injection of normal byoblasts into the skeletal muscle of DMD patients proved safe but ineffective with little or no new expression of dystrophin documented.
Recently, the Kunkel lab has isolated a group of cells called muscle side population (SP) cells based on their ability to efflux the DNA binding dye Hoechst. These SP cells are isolated by FACS and they can proliferate in culture. Adult skeletal muscle progenitors that exist within the skeletal muscle SP cells have been shown to extravasate from the circulation and contribute to the regeneration of muscle when injected via the tail vein or the femoral artery into non-irradiated murine models for DMD. Current efforts are focused on a better characterization of these cells and maximizing donor cell engraftment by developing more efficient transplantation methods.
Kunkel Research at HHMI
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Dr. Levy has been conducting basic and clinical research in the biochemical disorders for many years. The basic goal has been to better understand the pathophysiology of these metabolic disorders and to develop better treatments that would prevent the mental retardation and other complications. The major interest of his group currently and for the past two decades has been the disorder phenylketonuria (PKU) and maternal PKU.
The current involvement is in examining a novel treatment for PKU, the use of a cofactor known as tetrahydrobiopterin (BH4) that would stimulate the activity of phenylalanine hydroxylase (PAH), the deficient enzyme and basic defect in PKU. Should pharmacologic amounts of BH4 reduce the high blood phenylalanine levels in PKU, the severe restrictions of the diet for PKU could be relieved for the great benefit of many children and their families. Dr. Levy and his group lead an international study into the use of BH4 in PKU.
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Jonathan Picker's research is focused on the neurobiology of behavioral disorders. At the molecular level he is working on the role of amino acids on neuroreceptors. This work focuses around the NMDA receptor which plays a pivotal role in memory and emotional expression. His particular interest is in developmental factors which lead to the neurodevelopmental problems seen in disorders such as schizophrenia, Fragile X and Rett syndrome.
As director of the Fragile X Program, Dr Picker is also working to investigate various neuromodulatory factors involved in the causation and variability of this disorder. In collaboration with others, he is also in the process of developing interventional approaches to help affected individuals and their families.
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The Walsh laboratory is interested in genes that regulate the development and function of the human cerebral cortex. Mutations in these genes cause autism and epilepsy as well as mental retardation and other learning disorders. Not only are these genes vital to the normal development of the cortex but also many appear to have been altered evolutionarily to allow the unique aspects of the brain that underlie human cognitive abilities. The Walsh laboratory collaborates with physicians all over the world, often in areas such as the Middle East where large family sizes and unique populations are more favorable for genetic analysis.
Recent work has been in identifying and studying the function of three genes that cause the human cerebral cortex to be reduced in size and identifying a gene for a disorder of neuronal migration in the human brain associated with mental retardation and epilepsy. The lab has also been busy describing the clinical and radiological features of a newly identified condition and mapping the gene involved.
The Walsh Laboratory
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