1. Duchenne Muscular DystrophyDuchenne Muscular Dystrophy
Curtis KendallCurtis Kendall
December 5, 2006December 5, 2006

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

3. Clinical FeaturesClinical Features
Genotype of DMDGenotype of DMD
 Females carry the DMD gene on the XFemales carry the DMD gene on the X
chromosome.chromosome.
 Females are carriers and have a 50%Females are carriers and have a 50%
chance of transmitting the disease inchance of transmitting the disease in
each pregnancy.each pregnancy.
 Sons who inherit the mutation willSons who inherit the mutation will
have the disease.have the disease.
 Daughters that inherit the mutationDaughters that inherit the mutation
will be carriers.will be carriers.
 The DMD gene is located on the Xp 21The DMD gene is located on the Xp 21
band of the X chromosome.band of the X chromosome.
 Mutations which affect the DMD gene.Mutations which affect the DMD gene.
 96% are frameshift mutations96% are frameshift mutations
 30% are new mutations30% are new mutations
 10-20% of new mutations occur in the10-20% of new mutations occur in the
gametocyte (sex cell, will be pass ongametocyte (sex cell, will be pass on
to the next generation).to the next generation).
 The most common mutation areThe most common mutation are
repeats of the CAG nucleotides.repeats of the CAG nucleotides.

4. Genotype of DMDGenotype of DMD
(Cont.)(Cont.)
 During the translocation process, a mutationDuring the translocation process, a mutation
occurs.occurs.
 Mutations leading to the absence of dystrophinMutations leading to the absence of dystrophin
 Very Large Deletions (lead to absence of dystrophin)Very Large Deletions (lead to absence of dystrophin)
 Mutations causing reading errors (causes aMutations causing reading errors (causes a
degraded, low functioning DMD protein molecule)degraded, low functioning DMD protein molecule)
 Stop mutationStop mutation
 Splicing mutationSplicing mutation
 DuplicationDuplication
 DeletionDeletion
 Point MutationsPoint Mutations

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

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

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

8. Allelic VariantsAllelic Variants
DiseaseDisease MutationMutation Effect ofEffect of
MutationMutation
PhenotypePhenotype
Duchenne MuscularDuchenne Muscular
DystrophyDystrophy
Very Large DeletionsVery Large Deletions
caused by: Stopcaused by: Stop
mutationsmutations
Splicing mutationsSplicing mutations
DeletionsDeletions
DuplicationsDuplications
Severely FunctionallySeverely Functionally
Impaired DystrophinImpaired Dystrophin
ProteinProtein
As Discussed In PriorAs Discussed In Prior
SlidesSlides
Becker MuscularBecker Muscular
DystrophyDystrophy
Deletion or DuplicationDeletion or Duplication
That Change In-FrameThat Change In-Frame
ExonsExons
Creates A Protein ThatCreates A Protein That
Is Partially FunctionalIs Partially Functional
Same As But LessSame As But Less
Sever Then DMD ButSever Then DMD But
Onset At Greater ThenOnset At Greater Then
7 Years Old7 Years Old
DMD Related DilatedDMD Related Dilated
CardiomyopathyCardiomyopathy
Effects The CardiacEffects The Cardiac
Muscle Promoter andMuscle Promoter and
The First ExonThe First Exon
No DystrophinNo Dystrophin
Transcriptions BeingTranscriptions Being
Carried Out In CardiacCarried Out In Cardiac
MuscleMuscle
Tachycardia (Fat HeartTachycardia (Fat Heart
Beat) Leads ToBeat) Leads To
Congestive HearCongestive Hear
FailureFailure
Limb-Girdle MuscularLimb-Girdle Muscular
DystrophyDystrophy
In Gene That EncodesIn Gene That Encodes
Scarcoglycans andScarcoglycans and
Other Proteins ofOther Proteins of
Muscle CellsMuscle Cells
Decrease InDecrease In
Scarcoglycans ProteinsScarcoglycans Proteins
Pelvic and ShoulderPelvic and Shoulder
Girdle Can Look LikeGirdle Can Look Like
DMD or BMDDMD or BMD

9. Allelic VariantsAllelic Variants
(Cont.)(Cont.)
DiseaseDisease MutationMutation Effect ofEffect of
MutationMutation
PhenotypePhenotype
Proximal MyotonicProximal Myotonic
MyopathyMyopathy
Repeats In The GeneRepeats In The Gene
That Encodes For ZincThat Encodes For Zinc
Finger Protein 9Finger Protein 9
Lack of Zinc FingerLack of Zinc Finger
Protein 9 CausesProtein 9 Causes
Weakness In MuscleWeakness In Muscle
CellsCells
Stiffness or Pain InStiffness or Pain In
Limb Girdle DistributionLimb Girdle Distribution
Myotonic DystrophyMyotonic Dystrophy Increase In CTGIncrease In CTG
Nucleotide RepeatsNucleotide Repeats
Repeats of CTG CauseRepeats of CTG Cause
Neurological DisordersNeurological Disorders
Frontal Balding,Frontal Balding,
Cataracts, Diabetes,Cataracts, Diabetes,
Distal Limb WeaknessDistal Limb Weakness
Emery-DreifussEmery-Dreifuss
Muscular DystrophyMuscular Dystrophy
(EDMD)(EDMD)
EMD That Codes ForEMD That Codes For
Emerin and LMNAEmerin and LMNA
Which Codes ForWhich Codes For
Lamins ALamins A
Lack of Specificity ofLack of Specificity of
The DystrophicThe Dystrophic
Changes Observed.Changes Observed.
Joint ContracturesJoint Contractures
Leading To MuscleLeading To Muscle
Weakness andWeakness and
Wasting Usually SomeWasting Usually Some
Cardiac InvolvementCardiac Involvement
Spinal MuscularSpinal Muscular
AtrophyAtrophy
Mutation In The SMNMutation In The SMN
GeneGene
Degeneration of MotorDegeneration of Motor
Neurons Which AreNeurons Which Are
Nerve Cells In TheNerve Cells In The
Spinal Cord.Spinal Cord.
Poor Muscle Tone,Poor Muscle Tone,
Absence of DeepAbsence of Deep
Tendon ReflexesTendon Reflexes

10. 3D Images of The Actin Binding3D Images of The Actin Binding
Sight Of DystrophinSight Of Dystrophin

11. BibliographyBibliography
 OMIMOMIM
 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

12. Bibliography (Cont.)Bibliography (Cont.)
 PubMedPubMed
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Role of nuclear lamina-cytoskeleton interactions in the maintenance of cellular strength.Role of nuclear lamina-cytoskeleton interactions in the maintenance of cellular strength.
Biochim Biophys Acta.Biochim Biophys Acta. 2006 Sep 19;2006 Sep 19;
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Nomoto K, Toda H.Nomoto K, Toda H.
Cardiac dystrophin abnormalities in Becker muscular dystrophy assessed byCardiac dystrophin abnormalities in Becker muscular dystrophy assessed by
endomyocardial biopsy.endomyocardial biopsy.
Am Heart J.Am Heart J. 1995 Apr;1995 Apr;
 Kanagawa M, Toda T.Kanagawa M, Toda T.
The genetic and molecular basis of muscular dystrophy: roles of cell-matrix linkage in theThe genetic and molecular basis of muscular dystrophy: roles of cell-matrix linkage in the
pathogenesis.pathogenesis.
J Hum Genet.J Hum Genet. 2006 Sep 13;2006 Sep 13;
 Beroud C, Tuffery-Giraud S, Matsuo M, Hamroun D, Humbertclaude V, Monnier N,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, CosseeMoizard MP, Voelckel MA, Calemard LM, Boisseau P, Blayau M, Philippe C, Cossee
M, Pages M, Rivier F, Danos O, Garcia L, Claustres MM, Pages M, Rivier F, Danos O, Garcia L, Claustres M
Multiexon skipping leading to an artificial DMD protein lacking amino acids from exon 45Multiexon 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.through 55 could rescue up to 63% of patients with Duchenne muscular dystrophy.
Hum Mutat.Hum Mutat. 2006 Oct 13;2006 Oct 13;
 Ervasti JM.Ervasti JM.
Dystrophin, its interactions with other proteins, and implications for muscular dystrophy.Dystrophin, its interactions with other proteins, and implications for muscular dystrophy.
Biochim Biophys Acta.Biochim Biophys Acta. 2006 Jun 7;2006 Jun 7;