Transcript Duchenne Muscular Dystrophy

Duchenne Muscular Dystrophy
Curtis Kendall
December 5, 2006
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.
Clinical Features
Genotype 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.
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
Clinical Features
Phenotype 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)
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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. IQ’s 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.
Molecular Makeup
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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)
DMD Gene and Dystrophin
Function
 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.
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
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
3D Images of The Actin Binding
Sight Of Dystrophin
Bibliography
 OMIM
 MUSCULAR DYSTROPHY, DUCHENNE TYPE; DMD
#310200 http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=310200
 DYSTROPHIN; DMD
#300377
http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?cmd=entry&id=300377
 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
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;