Here are a few of the labs working on Myotonic Dystrophy

Dr. Puymirat Quebec, Canada
The major aim of the Puymirat lab is to develop a genetic therapy for Steinert dystrophy. During the last few years, the Puymirat lab developed a genetic approach capable of restoring normal functions of the affected human muscle cell. Indeed, Steinert dystrophy is caused by an abnormal accumulation of RNA in the nucleus of muscle cells. The therapy developed by the Puymirat lab is based on the specific destruction of RNA using antisense RNA and ribozymes. The research group showed in vitro that specific destruction of mRNA restored normal functions of the cell. In vivo, intramuscular injection of vectors producing antisense RNA or ribozymes reduced the levels of mutated RNA by 80%. The team is currently studying the effectiveness of this therapy in mice carrying the pathology.

             The Puymirat laboratory is also interested in the study of mechanisms responsible for this pathology, particularly on the identification of abnormally produced proteins. Dr Puymirat’s research group is also studying mechanisms responsible for congenital forms of the disease. 

              In addition, Dr Puymirat’s team is interested in developing tools in order to quantify the deficit caused by this pathology and on the use of muscle imagery (MRI and PET scan) to quantify muscle functions. Researchers of the Puymirat lab also conduct clinical trials aimed at reducing the symptoms of the disease. Finally, Dr Jack Puymirat is responsible for the Provincial Network of Neurogenetics and for the clinical diagnosis laboratory.

Human genetic department

2705,  Laurier Boulevard. RC-9300. Quebec (Quebec) Canada. G1V 4G2. Phone: +1 (418) 654-2186. Fax: +1 (418) 654-2207.

E-mail: sec.genetique@crchul.ulaval.ca

Senator Paul Wellstone Muscular Dystrophy Research Center
Centers of Excellence

The National Institutes of Health (NIH) established centers of excellence for muscular dystrophy research through Congressional Acts passed in the years 2001 and 2008. The NIH currently funds six Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Centers (MDCRCs). The University of Rochester Medical Center (URMC) was one of the three centers nationwide designated as a MDCRC from 2003-2008. We have received additional support from 2008-2013.

The goals of MDCRCs are to establish research programs focused on major questions about muscular dystrophy. MDCRCs are designed to centralize the expertise, infrastructure and resources needed to conduct innovative, cross-disciplinary and multi-institutional research programs with state-of-the-art technologies. They serve to expand the resources available to investigators and to physicians diagnosing and treating people with muscle diseases and contribute to the training of new researchers for the muscular dystrophy field.

MDCRCs promote parallel research in three main areas:

• Basic research or studies that explore the cellular or “mechanisms’ of how muscular dystrophies develop and progress. For example, studies in the laboratory to measure muscle cells or to screen new drugs.
• Translational research to study how discoveries or drugs tested in laboratory test tubes and other research models “translate” or compare to the effects of these drugs in human studies.
• Clinical research to study drugs, devices, or other treatments in human subjects and to determine if these therapies are safe and beneficial to patients.

Strengths of the University of Rochester Medical Center MDCRC

• Comprised of world-renowned investigators and research professionals in the URMC Department of Neurology
• Linked to the NIH supported Clinical and Translational Science Institute at URMC – one of the first nationwide centers of excellence in translational research, designed to bring new preventive interventions, diagnostic procedures and treatments to patients and communities faster than ever before;
• Dedicated and well-characterized patients with myotonic dystrophy (DM) and patients with facioscapulohumeral muscular dystrophy (FSHD) who are eager to support research and to participate in clinical studies through a NIH sponsored National Registry.

Director

Richard T. Moxley III, MD

Co-director

Charles A. Thornton, MD

Executive Committee

Richard T. Moxley III, MD
Charles A. Thornton, MD
Maurice Swanson, PhD
Rabi Tawil, MD
Hugh Higgins

Contact Information

Tracy Forrester
University of Rochester Medical Center
601 Elmwood Ave, Box 673
Rochester, NY 14642
Phone: 585-275-7434
Email: tracy_forrester@urmc.rochester.edu

Last updated 5/18/2009

Tom Cooper Laboratory

The recent realization that most human genes generate multiple protein isoforms via alternative splicing has revealed an extensive degree of regulation that remains to be explored.

The Tom Cooper Lab is interested in understanding the mechanisms of this regulation, from how RNA binding proteins regulate splicing of individual pre-mRNAs to the signaling events that coordinate splicing networks during development.

We also study myotonic dystrophy, the most common form of adult onset muscular dystrophy, in which disrupted splicing regulation causes the primary features of the disease.

Tom Cooper, M.D.
S. Donald Greenberg Professor of Pathology
Office Phone: 713-798-3141
Lab Phone: 713-798-5021
Fax: 713-798-5838

 Andy Berglund Laboratory

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The primary goal of the Berglund lab is to understand how introns are recognized in the process of pre-mRNA splicing. Pre-mRNA splicing is conserved from yeast to humans and a complex molecular machine, the spliceosome, is responsible for removing introns from pre-mRNAs. The factors (U1 snRNP – an RNA-protein particle, U2AF65, U2AF35 and BBP/SF1) shown in the figure are the primary factors responsible for initial intron recognition. We are using both biochemical and biophysical techniques to study these RNA-RNA, RNA-protein and protein-protein interactions. These interactions are critical because without the correct choice of splice sites, truncated proteins or proteins with the wrong sequence would be produced. Incorrect splice site selection is thought to be responsible for 15% or more of human diseases.

We are characterizing these RNA-RNA and RNA-protein interactions from multiple organisms. These include the yeast Saccharomyces cerevisiae which is an excellent model system because the introns are small and apparently there is very little or no regulation of splicing. However, in humans, the regulation of pre-mRNA splicing is very important. Almost all genes in humans contain introns and many of these genes are regulated at the level of pre-mRNA splicing. This regulation frequently results in alternative splicing which suggests that although there are only approximately 25,000 genes in the human genome the number of proteins produced is much higher than this. The control of this regulation occurs through RNA sequences found in either the intron or exon acting as either repressor or enhancer elements to influence the percentage of intron removal, splice site selection, or exon skipping. The interplay of the factors that bind these enhancer/repressor elements and their interactions with the general splicing factors (U2AF65/35, BBP/SF1 and U1 snRNP, see figure) is another focus within the lab.
Myotonic Dystrophy

The splicing factor, muscleblind (MBNL), regulates alternative splicing by affecting splice site selection (figure). Myotonic dystrophy (a form of muscular dystrophy) occurs when MBNL does not properly function. The dysfunction of MBNL occurs in a novel manner in the disease state MBNL is mis-localized and cannot act on its target pre-mRNAs. MBNL is mis-localized by binding to CUG triplet expansion repeats in the 3′ UTR of the dystrophia myotonia protein kinase (DMPK) gene. Hundreds of CUG repeats are common in patients with myotonic dystrophy while unaffected individuals have 5-30 CUG repeats. Longer CUG repeats (1,000 or more) results in more MBNL protein being mis-localized and leads to a more serious form of myotonic dystrophy because the regulation of alternative splicing of various pre-mRNAs is more severely compromised due to the increasing amounts of mis-localized MBNL. Using biochemical and biophysical methods we are studying the interaction between MBNL and the triplet expansion CUG repeats as well as MBNL’s interactions with its normal pre-mRNA targets to gain insight into the molecular mechanisms of myotonic dystrophy and alternative splicing.

• Human and molecular genetics
• Cancer genetics
• Neurogenetics
• Genomics

Research in the Krahe laboratory focuses on the identification and characterization of human disease genes and their mutations/variants, including inherited cancer syndromes (Li-Fraumeni Syndrome) and the myotonic dystrophies (DM), by classic and molecular genetics and genomics approaches.

Li-Fraumeni syndrome (LFS) is a genetically heterogeneous, rare inherited cancer syndrome. Most cases are due to mutations in the tumor suppressor p53. We have mapped a novel LFS predisposition locus to 1q23, the gene for which we are identifying. In p53 and non-p53 LFS, there is evidence for risk modifiers and factors inaddition to the inherited susceptibility. We are using integrated approaches combining genomic and epigenomic profiling to dissect the complex genetic and epigenetic events underlying LFS tumorigenesis. To dissect the pathophysiological consequences of variant genes, we are generating suitable LFS mouse models. LFS predisposition and/or modifier genes may also be functionally important in other tumor types lacking a clear genetic predisposition. The molecular characterization and classification of sporadic cancers (head and neck and lung cancer, and gliomas) through genomics methodologies to identify genomic, epigenomic and transcriptomic changes underlying tumor initiation, progression and metastasis is another focus.

Myotonic dystrophy, themost common adult neuromuscular disorder, is caused by mutant (CTG)_DM1 or (CCTG)_DM2 expansions that when transcribed cause disease. It is unclear how these mutant (CUG)_DM1/(CCUG)_DM2 RNAs mediate their disease-causing effects at the molecular and cellular level. To dissect the pathophysiology, we are using functional genomics and molecular genetics approaches and have generated transgenic, knock-in and knock-out mouse models.

View a complete listof publications.

Biochemistry & Molecular Biology
Keck School of Medicine
Institute for Genetic Medicine

Research Topics

• Developmental Biology
• Cardiovascular & Skeletal Muscle Diseases
• DNA Replication, Repair, Modification, Neurogenetics

Research Overview

My laboratory is interested in the molecular defects that contribute to the development of myotonic dystrophy. The myotonic dystrophies, DM1 and DM2, are multi-symptom disorders characterized by a wide range of muscle and neurological defects. We are using both mouse genetics and biochemical approaches to understand the molecular basis of these diseases.

The genetic defects in DM1 and DM2 are expansions of CTG and CCTG repeat tracts located in untranslated regions of two genes, DMPK and ZNF9, located on chromosome 19q and 3q, respectively. DM1 is the more serious disorder, exhibiting both unique features and demonstrating increased incidence and severity of several symptoms shared between the two disorders. We are currently testing the following hypotheses:

(i) Unique features of DM1 arise from locus specific cis effects of CTG expansion

(ii) A dominant RNA mechanism underlies shared features of both diseases

(iii) Disruption of aberrant interactions between the muscleblind proteins and the mutant RNAs is sufficient to rescue pathological features that are common to both diseases.

Cis effects of CTG expansion in DM1: CTG expansions in DM1 patients have thus far been shown to cause stochastic decreases in the steady-state levels of two genes, DMPK and SIX5, which are located in the vicinity of the CTG tract. We are testing the hypothesis that locus specific cis effects of CTG expansion contribute to the increased severity and complexity of the symptoms exhibited by DM1 patients. This hypothesis predicts that inactivation of DMPK and SIX5 should result in partial DM1 phenotypes in model animals. To test this model, we have developed mice in which Dmpk and Six5 have been functionally inactivated. Analyses of these mouse strains demonstrate that decreased levels of Dmpk and Six5 result in a unique set of pathophysiological features that are observed in DM1 patients. Specifically, reduced Dmpk levels results in skeletal muscle weakness, ion channel defects and cardiac conduction disease while Six5 loss increases the incidence of congenital cataracts, cardiac hypertrophy and gonadal dysfunction. Defining the number of genes affected at the DM1 locus and understanding their contribution to the DM1 phenotype are current interests of the lab. These analyses will be carried out using a mouse model of DM1, in which expanded CTG tracts have been introduced into the corresponding mouse Dm1 locus.

RNA dominant mechanism: An RNA dominant mechanism has been shown to underlie the development of several pathological features that are common to both DM1 and DM2. Specifically, mutant RNAs encoding expanded CUG and CCUG repeat sequences are known to sequester the muscleblind family of proteins to form aberrant nuclear foci. We have shown that the muscleblind proteins are RNA splice regulators and that dysregulation of their activity results in RNA splice defects in DM patient cells. In ongoing experiments we are assessing the role of the muscleblind family of genes in DM by developing single and double mutants of the muscleblind family of genes in mice. In a parallel series of experiments we are attempting to understand the molecular basis of the toxicity associated with expanded CUG/CCUG tracts by functional characterization of the protein profile of DM nuclear foci using molecular and biochemical approaches.

Screening chemical libraries for small molecules that rescue DM pathology: We are currently developing molecular screens to identify small molecules that disaggregate DM foci in patient cells and allow a rescue of the DM associated splice defects. The effectiveness of such molecules in rescuing features of DM pathology will be further assessed in vivo using mouse models for DM that are under construction in my lab.

David Brook

Professor of Human Genetics, Faculty of Medicine & Health Sciences

Contact

• Room C14a Medical School
  Queen’s Medical Centre
  Nottingham ENGLAND
  NG7 2UH
  UK
• 0115 823 0345
• david.brook@nottingham.ac.uk

Biography

University of Manchester BSc 1979, University of Edinburgh PhD 1983, University of Wales College of Medicine Post-Doc 1982 – 1989, Massachusetts Institute of Technology Post-Doc 1989 – 1992, University of Nottingham Senior Lecturer 1992 – 1995, Professor 1995 – present, Head of the Institute of Genetics 2000 – 2003, Head of the School of Biology 2003 – 2008.

Teaching Summary

Human Molecular Genetics

Research Summary

Molecular genetic studies to identify genes involved in cardiac development: Holt-Oram syndrome (HOS) is an inherited disorder that affects the development of the heart and upper limb. Whilst HOS is… read more

Understanding the molecular basis of myotonic dystrophy

Myotonic dystrophy (DM) is the most common form of muscular dystrophy affecting adults. DM is caused by the expansion of a repeated DNA sequence, CTG, which is located in the 3? untranslated region of a gene DMPK. It is not known how the expansion of this repeat causes the pathophysiology of DM. There are two main theories. One possibility is that expansion of the repeat affects the expression of DMPK and neighbouring genes. The other possibility is that the DMPK RNA with an expanded repeat interacts with cellular proteins to produce a gain-of-function mutation. We are actively investigating both possible mechanisms.

The Pearson Lab

Christopher E. Pearson completed a Ph.D. (McGill University, 1994) studying mammalian DNA replication and protein interactions with cruciform-DNAs, proceeded to a post-doc (Texas Medical Center) elucidating the newly identified disease-mutation of trinucleotide repeat instability. During this time, Christopher discovered the elusive slipped-strand DNAs. Christopher is a Senior Scientist at The Hospital for Sick Children, Department of Genetics; an Associate Professor at the University of Toronto, Department of Medical Genetics & Microbiology; and a member of the Canadian Genetic Diseases Network.

The Pearson Lab studies the molecular mechanisms involved in genetic mutations in trinucleotide repeat sequences.  Instability (i.e., expansions) of trinucleotide repeats are responsible for numerous neurological, neurodegenerative, and neuromuscular disorders including myotonic dystrophy (the most common form of muscular dystrophy), Huntington’s disease and fragile X syndrome (the most common form of inherited mental retardation). Our research focus is identifying cis-elements and trans-factors as well as cellular mechanisms (i.e., DNA repair, DNA replication, and epigenetics) that are involved in disease-associated repeat instability. We use molecular, cellular and chromosomal systems including primate models, patient cells and tissues and transgenic mice in our studies.

Other USA Labs working on Myotonic Dystrophy

Andy Berglund – University of Oregon
Tom Cooper – Baylor College of Medicine
Ralph Krahe – MD Anderson Cancer Center
Mani Mahadevan – University of Virginia
Glenn Morris – Wolfson Center for Inherited Neuromuscular Disease
Jack Puymirat – University of Laval
Laura Ranum – University of Minnesota
Sita Reddy – Keck School of Medicine of USC
Maurice Swanson – University of Florida
Charles Thornton – University of Rochester Medical Center
Nikolai Timchenko – Baylor College of Medicine