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Archive - Jun 3, 2019

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Lithium Boosts Muscle Mass & Strength in Mouse Model of Rare Muscular Dystrophy (LGMD1D); Possible Therapeutic Target Identified

Standing up from a chair, climbing stairs, brushing one's hair – all can be a struggle for people with a rare form of muscular dystrophy that causes progressive weakness in the shoulders and hips. Over time, many such people lose the ability to walk or to lift their arms above their heads. This form of the disease, called limb girdle muscular dystrophy (LGMD), affects a few thousand people nationwide in the United States. As other rare illnesses, LGMD tends not to attract much attention from researchers and funding agencies, so progress toward developing therapies has been slow. But a team at Washington University School of Medicine in St. Louis that identified a subtype (LGMD1D) of the disease in 2012 has shown that lithium improves muscle size and strength in mice with this form of muscular dystrophy. The new findings, published in the April 2019 issue of Neurology Genetics, could lead to a drug for the disabling condition. The open-access article is titled “Lithium Chloride Corrects Weakness and Myopathology in a Preclinical Model of LGMD1D.” "There are no medications available for people with limb girdle muscular dystrophy, so we are very excited to have a good therapeutic target and a potential therapy," said senior author C. Chris Weihl, MD, PhD, a Professor of Neurology who treats people with muscular dystrophy at the university's Neuromuscular Disease Center. "This has been an amazing project. It all began when we diagnosed a patient with muscular dystrophy of unknown cause. Genetic sequencing then helped us identify a new subtype, and we've been able to take that all the way through to a possible therapy."

20 Gene Loci Are Newly Associated with Bipolar Disorder in Major International Study of Over 50,000 Subjects; New Gene Clues May Give More Refined Direction to Therapy Development

In the largest study of its kind, involving more than 50,000 subjects in 14 countries, researchers at the Icahn School of Medicine at Mount Sinai in New York City and more than 200 collaborating institutions have identified 20 new genetic associations with one of the most prevalent and elusive mental illnesses of our time--bipolar disorder. The study is reported in the May 2019 issue of Nature Genetics. A total of 30 associated loci (10 already known) were identified in the genome-wide association study. The elevated morbidity and mortality associated with bipolar disorder make it a major public health problem and a leading contributor to the global burden of disease. The identification of genes associated with bipolar disorder can help identify therapeutic targets for treatment and prevention. The title of the Nature Genetics article is “Genome-Wide Association Study Identifies 30 Loci Associated with Bipolar Disorder.” Bipolar disorder, a neuropsychiatric condition characterized by dramatic shifts in a person's mood, affects approximately 60 million people globally, 10 million of them in the United States. Unlike many other illnesses, bipolar disorder has been found to affect men, women, and people of all ethnic groups equally. While genetic and environmental factors have been demonstrated to play a role in the illness, the exact cause of bipolar disorder remains unknown. To identify genes associated with the disorder, researchers conducted a genome-wide association study (GWAS)--a study type used to look across the entire genome for differences in the genetic code that are associated with a particular trait, such as having a mental illness.

Body’s Response to Disease’s Basic Gene Defect Leads to Buildup of Mis-Produced Fat Cells That Causes Abrupt Decline in Muscle Function and Is Key to Sudden Onset of Symptoms in Limb-Girdle Muscular Dystrophy Type 2 (LGMD2B) in Young Adulthood

Research led by faculty at Children's National in Washington, DC, and published online on June 3, 2019 in Nature Communications, shows that the sudden appearance of symptoms in limb-girdle muscular dystrophy type 2B (LGMD2B) is a result of impaired communication between different cell types that facilitate repair in healthy muscle. The open-access article is titled “Fibroadipogenic Progenitors Are Responsible for Muscle Loss in Limb Girdle Muscular Dystrophy 2B.” Of particular interest are the fibro/adipogenic precursors (FAPs), cells that typically play a helpful role in regenerating muscle after injury by removing debris and enhancing the fusion of muscle cells into new myofibers. LGMD2B is caused by mutations in the DYSF gene that impair the function of dysferlin, a protein essential for repairing injured muscle fibers. Symptoms, like difficulty climbing or running, do not appear in patients until young adulthood. This late onset has long puzzled researchers, as the cellular consequences of dysferlin's absence are present from birth and continue through development, but do not impact patients until later in life. The study found that in the absence of dysferlin, muscle gradually increases the expression of the protein annexin A2 which, like dysferlin, facilitates repair of injured muscle fiber. However, increasing annexin A2 accumulates outside the muscle fiber and drives an increase in FAPs within the muscle and also influences these FAPs to differentiate into adipocytes, forming fatty deposits. Shutting down annexin A2 or blocking the adipocyte fate of FAPs using an off-the-shelf medicine arrests the fatty replacement of dysferlinopathic muscle.

Atlas of ~10,000 Genome Regions of Epigenetic Variation Between Individuals, But Consistent Across Different Tissues in Individuals, Established for DNA Methylation Marks Detectable in Blood; Work Should Aid Unraveling of Epigenetic Causes of Disease

More than 15 years after scientists first mapped the human genome, most diseases still cannot be predicted based on one's genes, leading researchers to explore epigenetic causes of disease. But the study of epigenetics cannot be approached in the same way as genetics, so progress has been slow. Now, researchers at the USDA/ARS Children's Nutrition Research Center at Baylor College of Medicine and Texas Children's Hospital have determined a unique fraction of the genome that scientists should focus on. Their report, which provides a "treasure map" to accelerate research in epigenetics and human disease, was published online on June 3, 2019 in Genome Biology. The open-access article is titled “A Genomic Atlas of Systemic Interindividual Epigenetic Variation in Humans.” Epigenetics is a system for molecular marking of DNA that tells the different cells in the body which genes to turn on or off in that cell type. But the cell-specific nature of epigenetics makes it challenging to study. Whereas a blood sample can be used to “genotype” an individual, most epigenetic marks in blood DNA provide no clues about epigenetic dysregulation in other parts of the body, such as the brain or heart. The authors note the following. “DNA methylation is thought to be an important determinant of human phenotypic variation, but its inherent cell type specificity has impeded progress on this question. At exceptional genomic regions, interindividual variation in DNA methylation occurs systemically. Like genetic variants, systemic interindividual epigenetic variants are stable, can influence phenotype, and can be assessed in any easily biopsiable DNA sample. We describe an unbiased screen for human genomic regions at which interindividual variation in DNA methylation is not tissue-specific.” Senior author Robert A.