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Molecular Genetics of Muscle Disorders PowerPoint Presentation

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Description : Check out this medical PowerPoint presentation titled "Molecular Genetics of Muscle Disorders”.

This medical PowerPoint presentation is about muscle disorders, also known as neuromuscular disorders. Muscle disorders refer to a group of conditions that affect the muscles and the nerves that control them. Molecular genetics has played a significant role in advancing our understanding of the underlying genetic causes of various muscle disorders. Here are some examples:

Duchenne muscular dystrophy (DMD): DMD is a severe and progressive muscle disorder caused by mutations in the DMD gene, which encodes for the protein dystrophin. Dystrophin is critical for maintaining the structural integrity of muscle fibers. Without dystrophin, the muscle fibers become fragile and easily damaged, leading to muscle weakness and wasting. Genetic testing can identify mutations in the DMD gene, and advances in gene therapy hold promise for potential treatments.
Myotonic dystrophy: Myotonic dystrophy is a genetic disorder caused by mutations in either the DMPK or CNBP genes. These mutations lead to the production of abnormal RNA molecules that interfere with normal cellular processes, leading to muscle weakness and wasting, as well as other symptoms such as heart problems and cognitive impairment.
Spinal muscular atrophy (SMA): SMA is a genetic disorder caused by mutations in the SMN1 gene, which encodes for the survival motor neuron protein. This protein is critical for the survival and function of motor neurons, which control muscle movement. Without enough functional SMN protein, motor neurons die, leading to muscle weakness and wasting. Advances in gene therapy have led to the approval of the first-ever treatment for SMA in 2019.
Pompe disease: Pompe disease is a rare genetic disorder caused by mutations in the GAA gene, which encodes for the enzyme acid alpha-glucosidase. This enzyme is responsible for breaking down glycogen, a complex sugar molecule that is stored in cells for energy. In Pompe disease, the lack of functional acid alpha-glucosidase leads to the buildup of glycogen in muscle cells, causing muscle weakness and damage.

In conclusion, molecular genetics has significantly contributed to our understanding of muscle disorders and has led to the development of potential treatments for some of these conditions. Further research in this field holds the promise of identifying new genes and pathways involved in these disorders and developing more effective therapies for patients.

Tags : muscle disorders, neuromuscular disorders, Molecular genetics, Duchenne muscular dystrophy, Myotonic dystrophy, Spinal muscular atrophy, Neurology, Neurology PowerPoint presentation

Published on : Jun 20, 2023 | Views : 1050 | Downloads : 0

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Slide 1-

Molecular Genetics of Muscle Disorders Chapter 13 (pp. 369-376) 650 different Muscles !
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650 different Muscles ! Skeletal Muscle For locomotion (voluntary) Cardiac Muscle Heart muscles (involuntary) Smooth Muscle Lining the wall of interior organs (involuntary)
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More than 1000 genes required for proper muscle formation and functioning: Providing energy to the cell (respiration) Structure of muscles Involved in contraction process Muscular Dystrophy Mutations have been found in all of these categories
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Figure 13.1 Muscle Cells: Can be very long (12 inches) Multinucleate
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One nucleus per cell Many nuclei per cell because The cell is soooo long! One nucleus per cell
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Calcium enters the cell after receiving a nerve impulse to do so, and leaves the cell during the ‘relaxation stage’.
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Thin Myofilaments Thick Myofilaments
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Mitochondria
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Figure 13.3 Non-covalent interactions Signaling system
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Extracellular Matrix (collagen, etc.)
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All linked to a Nucleus
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A lot of good, easy-to-understand information is at this < hyperlink
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Four Domains
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Binds to Actin (240 amino acids) Four Domains
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Binds to Actin (240 amino acids) Central rod 24 repeats of ≈125 amino acids = 3000 a.a. Binds to Syntrophins, Dystrobrevin, etc. (420 amino acids) Four Domains
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Binds to Actin (240 amino acids) Central rod 24 repeats of ≈125 amino acids = 3000 a.a. Binds to Dystroglycan (280 amino acids) Four Domains
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Binds to Actin (240 amino acids) Central rod 24 repeats of ≈125 amino acids = 3000 a.a. Binds to Dystroglycan (280 amino acids) Binds to Syntrophins, Dystrobrevin, etc. (420 amino acids) Four Domains
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X-Linked, Recessive 1 in 3300 male births Few symptoms until about 5 1/3-1/2 have learning disability First, not able to “keep up” with other children Then will start to “waddle” Then starts to walk on toes Curvature of spine Then uses hands to hold self up Wheelchair only by 10 years Chest muscles weaken, making breathing difficult Respiratory failure (death) at 17 Duchenne Muscular Dystrophy Heart & Lung muscles weaken
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Muscles of shoulders & pelvis weaken first
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Becker Muscular Dystrophy A milder form of the same disease (and mutation of the same gene, Dystrophin) 1 in 30,000 males Affected males live longer
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Largest gene found in nature = 2.4 million bases Dystrophin 79 Exons
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Largest gene found in nature = 2.4 million bases Dystrophin 79 Exons Duchenne Muscular Dystrophy is generally caused by frameshift (or missense mutations) at the 3rd or 4th domains Causing a truncated protein Becker Muscular Dystrophy is generally caused by internal parts of the proteing being missing cDNA cloned in 1987
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How would you go about cloning this gene?
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2/3 of cases are inherited, 1/3 are sporadic (new mutations) Second human gene cloned by “Positional Cloning” (the third was Cystic Fibrosis gene) Dystrophin Lots of different labs were looking for this gene, and they took different approaches
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Biopsy of normal and DMD muscle And did gel electrophoresis of the proteins 1987
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Biopsy of normal and DMD muscle And did gel electrophoresis of the proteins 1987 Observed a lack of large MW proteins in DMD muscles
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Immunoblots “Western Blots”
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Normal DMD
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Cytogenetic analysis of one DMD patient showed a thinner chromosome band here.
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Made Hamster Somatic Cell Hybrids with that guy’s Chromosome X
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Made Hamster Somatic Cell Hybrids with this guy’s Chromosome X And probed with 20 random pieces of DNA from a genomic library of Chromosome X (from a healthy person). ….19 probes hybridized, 1 didn’t !
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Koenig, et al., 1987 Cell, Vol. 50: 509. Example of a DMD RFLP Digested with XmnI
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As they got closer to figuring out that the DMD gene was in the middle of the short arm of the X chromosome they used various fragments of the Genomic Library to screen a cDNA Library. The cDNA Library was made from fetal muscle tissue (female).
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A good candidate for a cDNA for DMD would be something large !
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1987 Reported that the most common difference between the healthy DMD gene and the mutated one was a 2000 bp deletion….it was present in about half of 104 boys with the disease.
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1988
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Binds to Actin (240 amino acids) Central rod 24 repeats of ≈125 amino acids = 3000 a.a. Binds to Dystroglycan (280 amino acids) Binds to Syntrophins, Dystrobrevin, etc. (420 amino acids) Four Domains
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Was initially mysterious because the smaller delection was associated With the more-severe form of MD. 76 exons
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http://www.bms.ed.ac.uk/research/others/smaciver/MD%20cause.htm
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The role of muscle biopsy in analysis of the dystrophin gene in Duchenne muscular dystrophy: experience of a national referral centre.Tuffery-Giraud S, Saquet C, Chambert S, Echenne B, Marie Cuisset J, Rivier F, Cossee M, Philippe C, Monnier N, Bieth E, Recan D, Antoinette Voelckel M, Perelman S, Lambert JC, Malcolm S, Claustres M.Laboratoire de Genetique Moleculaire et Chromosomique, Institut Universitaire de Recherche Clinique (IURC), CHU de Montpellier, 641 avenue du Doyen G. Giraud, 34093 Montpellier Cedex 5, France. tuffery@igh.cnrs.fr At the DNA level: (89 cases) Substitution = 57% Deletion = 32% Duplication = 9% Insertion =2% At Protein Level: Frameshift = 55% Nonsense = 39% Deletion = 6% * Our textbook says 65% deletions
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2003 79 Exons in all
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Healthy muscles DMD muscles http://www.neuro.wustl.edu/neuromuscular/pathol/dmdpath.htm * Remember this protein is fairly near the cell surface Cytochemical staining for Dystrophin makes diagnosis fast
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What can be done with boys with DMD? At early stages Physical Therapy Splints, Crutches, Wheelchairs Surgery At later stages Cardiological medicines Assisted breathing devices (later stages) Prednisone, a corticosteroid, similar to a hormone produced by the adrenal glands. Lots of side effects: weight gain, bone brittleness, cataracts, mood changes… …more aggressive)
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Used adenoviral vector
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Hemophilia Color Blindness High Blood Pressure
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Largest gene found in nature = 2.4 million bases Dystrophin 79 Exons Alternative splicing
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Multiplex PCR PCR using multiple pairs of primers (representing exons) 9 primer pairs
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