Duchenne Muscular Dystrophy

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Duchenne Muscular Dystrophy

• Curtis Kendall
• December 5, 2006

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Duchenne Muscular Dystrophy Facts

• DMD affects mostly males at a rate of 1 in 3,500
  births.
• There are over 200 types of mutations that can
  cause any one of the forms of muscular dystrophy.
• There are also mutations that occur within the
  same gene that cause other disease types.
• DMD is the most severe and common type of
  muscular dystrophy.
• DMD is characterized by the wasting away of
  muscles.
• DMD is the most aggressive form of muscular
  dystrophy.
• Diagnosis in boys usually occurs between 16
  months and 8 years.
• Parents are usually the first to notice problem.
• Death from DMD usually occurs by age of 30.

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Clinical FeaturesGenotype of DMD

• Females carry the DMD gene on the X chromosome.
• Females are carriers and have a 50 chance of
  transmitting the disease in each pregnancy.
• Sons who inherit the mutation will have the
  disease.
• Daughters that inherit the mutation will be
  carriers.
• The DMD gene is located on the Xp 21 band of the
  X chromosome.
• Mutations which affect the DMD gene.
• 96 are frameshift mutations
• 30 are new mutations
• 10-20 of new mutations occur in the gametocyte
  (sex cell, will be pass on to the next
  generation).
• The most common mutation are repeats of the CAG
  nucleotides.

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Genotype of DMD(Cont.)

• During the translocation process, a mutation
  occurs.
• Mutations leading to the absence of dystrophin
• Very Large Deletions (lead to absence of
  dystrophin)
• Mutations causing reading errors (causes a
  degraded, low functioning DMD protein molecule)
• Stop mutation
• Splicing mutation
• Duplication
• Deletion
• Point Mutations

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Clinical FeaturesPhenotype of DMD

• Delays in early childhood stages involving muscle
  use, in 42 of patients.
• Delays in standing alone
• Delays in sitting without aid
• Delays in walking (12 to 24 months)
• Toe walking or flat footednees.
• Child has a hard time climbing.
• Learning difficulties in 5 of patients.
• Speech problems in 3 of patients.
• Leg and calf pain.
• Mental development is impaired. IQs usually
  below 75 points.
• Memory problems
• Carrying out daily functions
• Increase in bone fractures due to the decrease in
  bone density.
• Increase in serum CK (creatine phosphokinase)
  levels up to 10 times normal amounts.
• Wheelchair bound by 12 years of age.
• Cardiomyopathy at 14 to 18 years.
• Few patients live beyond 30 years of age.
• Reparatory problems and cardiomyopathy leading to
  congestive heart failure are the usual cause of
  death.

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Molecular Makeup

• There are 79 exons which makeup 0.6 of the
  entire gene.
• There are 8 promoters (binding sights).
• Introns make up 99.4 of the entire gene.
• Genomic DNA 2.2 million base pairs.
• N-terminal or actin binding sight binds
  dystrophin to membranes surrounding striated
  muscle fiber.
• Rod Domain contains 24 proteins that repeat and
  maintain molecular structure.
• It is thought to give the rod its flexibility.
• The main rod is interrupted by 4 hinge regions.
• The cysteine-rich domain regulates ADAM protease
  which are cell membrane anchors that are
  important in maintaining cell shape and
  structure.
• The C-terminal contains the syntrophin binding
  sight (for binding internal cellular components)

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DMD Gene and DystrophinFunction

• The DMD gene encodes for the protein dystrophin,
  found in muscle cells and some neurons.
• Dystrophin provides strength to muscle cells by
  linking the internal cytoskeleton to the surface
  membrane.
• Without this structural support, the cell
  membrane becomes permeable. As components from
  outside the cell are allowed to enter the
  internal pressure of the cell increases until the
  cell bursts and dies.
• Under normal wear and tear stem cells within the
  muscle regenerate new muscle cells and repair the
  damage.
• In DMD the damage to muscle cells is so extreme
  that the supply of stem cells are exhausted and
  repair can no longer occur.

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Allelic Variants
Disease Mutation Effect of Mutation Phenotype
Duchenne Muscular Dystrophy Very Large Deletions caused by Stop mutations Splicing mutations Deletions Duplications Severely Functionally Impaired Dystrophin Protein As Discussed In Prior Slides
Becker Muscular Dystrophy Deletion or Duplication That Change In-Frame Exons Creates A Protein That Is Partially Functional Same As But Less Sever Then DMD But Onset At Greater Then 7 Years Old
DMD Related Dilated Cardiomyopathy Effects The Cardiac Muscle Promoter and The First Exon No Dystrophin Transcriptions Being Carried Out In Cardiac Muscle Tachycardia (Fat Heart Beat) Leads To Congestive Hear Failure
Limb-Girdle Muscular Dystrophy In Gene That Encodes Scarcoglycans and Other Proteins of Muscle Cells Decrease In Scarcoglycans Proteins Pelvic and Shoulder Girdle Can Look Like DMD or BMD
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Allelic Variants(Cont.)
Disease Mutation Effect of Mutation Phenotype
Proximal Myotonic Myopathy Repeats In The Gene That Encodes For Zinc Finger Protein 9 Lack of Zinc Finger Protein 9 Causes Weakness In Muscle Cells Stiffness or Pain In Limb Girdle Distribution
Myotonic Dystrophy Increase In CTG Nucleotide Repeats Repeats of CTG Cause Neurological Disorders Frontal Balding, Cataracts, Diabetes, Distal Limb Weakness
Emery-Dreifuss Muscular Dystrophy (EDMD) EMD That Codes For Emerin and LMNA Which Codes For Lamins A Lack of Specificity of The Dystrophic Changes Observed. Joint Contractures Leading To Muscle Weakness and Wasting Usually Some Cardiac Involvement
Spinal Muscular Atrophy Mutation In The SMN Gene Degeneration of Motor Neurons Which Are Nerve Cells In The Spinal Cord. Poor Muscle Tone, Absence of Deep Tendon Reflexes
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3D Images of The Actin Binding Sight Of Dystrophin
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Bibliography

• OMIM
• MUSCULAR DYSTROPHY, DUCHENNE TYPE DMD310200
  http//www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id
  310200
• DYSTROPHIN DMD
• 300377 http//www.ncbi.nlm.nih.gov/entrez/dispomi
  m.cgi?cmdentryid300377
• Bookshelf
• Genes and disease. Bethesda (MD) National
  Library of Medicine
• Introduction to Genetic Analysis. 7th ed.
  Griffiths, Anthony J.F. Miller, Jeffrey H.
  Suzuki, David T. Lewontin, Richard C. Gelbart,
  William M. New York c1999.
• Human Molecular Genetics 2 2nd ed. Strachan, Tom
  and Read, Andrew P. New York and London c1999
• GeneReviews Editor-in-chief Pagon, Roberta A.
  Associate editors Cassidy, Suzanne B. Bird,
  Thomas C. Dinulos, Mary Beth Feldman, Gerald
  L. Smith, Richard J.H. Dolan, Cynthia R.
  Technical editor Baskin, Patricia K. Seattle
  (WA) University of Washington 1993-2006

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Bibliography (Cont.)

• PubMed
• Houben F, Ramaekers FC, Snoeckx LH, Broers JL.
• Role of nuclear lamina-cytoskeleton interactions
  in the maintenance of cellular strength.
• Biochim Biophys Acta. 2006 Sep 19
• Maeda M, Nakao S, Miyazato H, Setoguchi M, Arima
  S, Higuchi I, Osame M, Taira A, Nomoto K, Toda H.
• Cardiac dystrophin abnormalities in Becker
  muscular dystrophy assessed by endomyocardial
  biopsy.
• Am Heart J. 1995 Apr
• Kanagawa M, Toda T.
• The genetic and molecular basis of muscular
  dystrophy roles of cell-matrix linkage in the
  pathogenesis.
• J Hum Genet. 2006 Sep 13
• Beroud C, Tuffery-Giraud S, Matsuo M, Hamroun D,
  Humbertclaude V, Monnier N, Moizard MP, Voelckel
  MA, Calemard LM, Boisseau P, Blayau M, Philippe
  C, Cossee M, Pages M, Rivier F, Danos O, Garcia
  L, Claustres M
• Multiexon skipping leading to an artificial DMD
  protein lacking amino acids from exon 45 through
  55 could rescue up to 63 of patients with
  Duchenne muscular dystrophy.
• Hum Mutat. 2006 Oct 13
• Ervasti JM.
• Dystrophin, its interactions with other proteins,
  and implications for muscular dystrophy.
• Biochim Biophys Acta. 2006 Jun 7