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Human Genome News Archive Edition

Human Genome News, March 1992; 3(6)

Researchers Find Myotonic Dystrophy Gene

Only 2 weeks after announcing that specific genetic alterations on chromosome 19 had been linked to myotonic dystrophy, research teams reported that they had almost simultaneously pinpointed the gene responsible for this complex heritable muscular disorder. Papers on the structural defect in the locus appeared in Nature on February 5. Subsequent reports on finding the gene were published in Cell on February 21 and in Science on March 6.

Investigators showed that the structural defect associated with myotonic dystrophy may grow larger with each generation and that the increase in size is associated with the severity of the disease. The enlarged gene area, consisting of a trinucleotide repeat (CTG) in the DNA sequence, is usually copied 5 to 30 times in people without myotonic dystrophy. Researchers found between 50 and several thousand copies of CTG in 95 to 98% of people with myotonic dystrophy symptoms, with the larger number of repeats appearing in the most severely affected patients. These findings build on those made last year for the gene that causes the fragile X syndrome (an inherited form of mental retardation).

Three sets of the investigators, who collaborated during the past 4 years to find the defect, described their results in separate papers in Nature. These groups were the following:

  1. An eight-person Lawrence Livermore National Laboratory (LLNL) team, led by Pieter de Jong, that worked with groups headed by Robert G. Korneluk (Children's Hospital of Eastern Ontario, Canada) and Bé Wieringa (University of Nijmegen, Netherlands).
  2. A group headed by Keith Johnson (Department of Anatomy of Charing Cross and Westminster Medical School, London).
  3. A collaborative effort between a team led by Duncan J. Shaw, Peter S. Harper, and Helen Harley (Institute of Medical Genetics, University of Wales College of Medicine, Cardiff) and another headed by David Brook and David Housman (Massachusetts Institute of Technology Center for Cancer Research).

Subsequently, the researchers listed in the teams above and C. Thomas Caskey and Henry Epstein (Baylor College of Medicine) published the Science and Cell papers that pinpointed the gene's location.

U.S. Secretary of Energy James D. Watkins congratulated members of the DOE-funded LLNL Human Genome Center and noted, "This is one of the early fruits of the Human Genome Project, and we can expect to see these advances coming with increasing frequency in the years to come."

Discovery of the gene should lead to the development of tests for earlier detection of this normally late-onset autosomal dominant disease, including detection before symptoms appear. Knowledge of the gene's normal function will allow a better assessment of the defective gene's consequences and possibly lead to improved diagnostic procedures and treatment methods for the disorder, which is estimated to appear in at least 1 in 8000 people worldwide each year.

In addition to the DOE Human Genome Program, the NIH National Center for Human Genome Research, the Muscular Dystrophy Association (MDA) of United States and Canada, the Muscular Dystrophy Group of Great Britain, the Eurogene European Community Genome Program, the Wellcome Trust, and several other international organizations supported this work.

Most of the mapping was done using cosmid clones produced at LLNL, and a major portion of the mapping was performed by LLNL scientists who focused their study on the middle of chromosome 19. To link the work of Korneluk and Wieringa, who were mapping the chromosome from opposite ends, de Jong and Cara Aslanidas (LLNL) supplied both groups with key recombinant DNA clones containing the segment with the defect. LLNL investigators identified yeast artificial chromosome (YAC) clones containing the defect, using a collection produced by Maynard Olson's group at Washington University in St. Louis. These unstable YACs were used to isolate the appropriate stable cosmid clones.

Anthony Carrano, Director of the LLNL Human Genome Center, noted that LLNL has a full suite of resources to assist in identifying, isolating, and mapping genes for chromosome 19. These include a foundation chromosome 19 cosmid contig map spanning an estimated 80% of the chromosome; high-density cosmid and YAC filters to assist collaborators in mapping genes; a chromosome 19 database accessible via Internet; and chromosome flow-sorting technology to create specialized libraries as part of the National Laboratory Gene Library Project.

Myotonic dystrophy, one of many heritable muscular diseases, causes spasms, weakness, and wasting in voluntary muscles and often produces difficulty in relaxing muscles (myotonia). A characteristic of this disease, which was first described in the early 1900s, is the highly variable severity of the symptoms, even among affected members of a single family.

Also known as dystrophia myotonica and Steinert's disease, myotonic dystrophy affects both men and women and usually appears in adolescence or early adulthood, although at least one often-fatal form causes symptoms that are noticeable at birth. The disease can cause heart problems, gastrointestinal complications, cataracts, premature balding, mental slowness, and sleep disorders; affected individuals may die of heart or respiratory failure in their 50s or 60s.

Another widespread muscular disorder is Duchenne muscular dystrophy, a childhood disease that is linked to the X chromosome and almost always affects males. Symptoms appear within the first 5 years, and the disease progresses very rapidly, with death occurring in the patient's late 20s. The gene responsible for Duchenne was found in 1986 in the laboratories of Louis Kunkel (Harvard Medical School), Kay Davies (John Radcliffe Hospital, Oxford, England), and Ronald Worton (Hospital for Sick Children, Toronto, Canada) [Monaco et al., Nature 323, 646-50 (Oct. 16, 1986)]. About 40 neuromuscular disorders are currently targeted by research efforts sponsored by the American MDA and other funding organizations.

Myotonic dystrophy contact:

  • Jim Brown (MDA)
    Tucson, Arizona


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Human Genome Project 1990–2003

The Human Genome Project (HGP) was an international 13-year effort, 1990 to 2003. Primary goals were to discover the complete set of human genes and make them accessible for further biological study, and determine the complete sequence of DNA bases in the human genome. See Timeline for more HGP history.

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