Duchenne Muscular DystrophyDuchenne Muscular Dystrophy

Curtis KendallCurtis Kendall

December 5, 2006December 5, 2006

Duchenne Muscular Dystrophy Duchenne 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 cause There 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 that There 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 muscular DMD 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 months Diagnosis 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.

Clinical FeaturesClinical FeaturesGenotype of DMDGenotype of DMD

Females carry the DMD gene on the X Females 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 in chance of transmitting the disease in each pregnancy.each pregnancy.

Sons who inherit the mutation will Sons who inherit the mutation will have the disease.have the disease.

Daughters that inherit the mutation Daughters that inherit the mutation will be carriers.will be carriers.

The DMD gene is located on the Xp 21 The 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 the 10-20% of new mutations occur in the

gametocyte (sex cell, will be pass on gametocyte (sex cell, will be pass on to the next generation).to the next generation).

The most common mutation are The most common mutation are repeats of the CAG nucleotides.repeats of the CAG nucleotides.

Genotype of DMDGenotype of DMD(Cont.)(Cont.)

During the translocation process, a mutation During 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 a Mutations 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

Clinical FeaturesClinical FeaturesPhenotype 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 times Increase 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 are Reparatory problems and cardiomyopathy leading to congestive heart failure are the usual cause of death.the usual cause of death.

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 membranes N-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 molecular Rod 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 cell The cysteine-rich domain: regulates ADAM protease which are cell membrane anchors that are important in maintaining cell shape and membrane anchors that are important in maintaining cell shape and structure.structure.

The C-terminal: contains the syntrophin binding sight (for binding internal The C-terminal: contains the syntrophin binding sight (for binding internal cellular components)cellular components)

DMD Gene and DystrophinDMD Gene and DystrophinFunctionFunction

The DMD gene encodes for the protein The DMD gene encodes for the protein dystrophin, found in muscle cells and some dystrophin, found in muscle cells and some neurons.neurons.

Dystrophin provides strength to muscle cells by Dystrophin provides strength to muscle cells by linking the internal cytoskeleton to the surface linking the internal cytoskeleton to the surface membrane.membrane.

Without this structural support, the cell membrane Without this structural support, the cell membrane becomes permeable. As components from outside becomes permeable. As components from outside the cell are allowed to enter the internal pressure the 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 the Under normal wear and tear stem cells within the muscle regenerate new muscle cells and repair the muscle regenerate new muscle cells and repair the damage.damage.

In DMD the damage to muscle cells is so extreme In DMD the damage to muscle cells is so extreme that the supply of stem cells are exhausted and that the supply of stem cells are exhausted and repair can no longer occur.repair can no longer occur.

Allelic VariantsAllelic VariantsDiseaseDisease MutationMutation Effect of Effect of

MutationMutationPhenotypePhenotype

Duchenne Muscular Duchenne Muscular DystrophyDystrophy

Very Large Deletions Very Large Deletions caused by: Stop caused by: Stop

mutationsmutations

Splicing mutationsSplicing mutations

DeletionsDeletions

DuplicationsDuplications

Severely Functionally Severely Functionally Impaired Dystrophin Impaired Dystrophin

ProteinProtein

As Discussed In Prior As Discussed In Prior SlidesSlides

Becker Muscular Becker Muscular DystrophyDystrophy

Deletion or Duplication Deletion or Duplication That Change In-Frame That Change In-Frame

ExonsExons

Creates A Protein That Creates A Protein That Is Partially Functional Is Partially Functional

Same As But Less Same As But Less Sever Then DMD But Sever Then DMD But

Onset At Greater Then Onset At Greater Then 7 Years Old7 Years Old

DMD Related Dilated DMD Related Dilated Cardiomyopathy Cardiomyopathy

Effects The Cardiac Effects The Cardiac Muscle Promoter and Muscle Promoter and

The First Exon The First Exon

No Dystrophin No Dystrophin Transcriptions Being Transcriptions Being

Carried Out In Cardiac Carried Out In Cardiac MuscleMuscle

Tachycardia (Fat Heart Tachycardia (Fat Heart Beat) Leads To Beat) Leads To

Congestive Hear Congestive Hear FailureFailure

Limb-Girdle Muscular Limb-Girdle Muscular DystrophyDystrophy

In Gene That Encodes In Gene That Encodes Scarcoglycans and Scarcoglycans and Other Proteins of Other Proteins of

Muscle CellsMuscle Cells

Decrease In Decrease In Scarcoglycans ProteinsScarcoglycans Proteins

Pelvic and Shoulder Pelvic and Shoulder Girdle Can Look Like Girdle Can Look Like

DMD or BMDDMD or BMD

Allelic VariantsAllelic Variants(Cont.)(Cont.)

DiseaseDisease MutationMutation Effect of Effect of MutationMutation

PhenotypePhenotype

Proximal MyotonicProximal Myotonic

MyopathyMyopathyRepeats In The Gene Repeats In The Gene

That Encodes For Zinc That Encodes For Zinc Finger Protein 9Finger Protein 9

Lack of Zinc Finger Lack of Zinc Finger Protein 9 Causes Protein 9 Causes

Weakness In Muscle Weakness In Muscle CellsCells

Stiffness or Pain In Stiffness or Pain In Limb Girdle Distribution Limb Girdle Distribution

Myotonic DystrophyMyotonic Dystrophy Increase In CTG Increase In CTG Nucleotide Repeats Nucleotide Repeats

Repeats of CTG Cause Repeats of CTG Cause Neurological DisordersNeurological Disorders

Frontal Balding, Frontal Balding, Cataracts, Diabetes, Cataracts, Diabetes,

Distal Limb WeaknessDistal Limb Weakness

Emery-Dreifuss Emery-Dreifuss Muscular Dystrophy Muscular Dystrophy

(EDMD)(EDMD)

EMD That Codes For EMD That Codes For Emerin and LMNA Emerin and LMNA Which Codes For Which Codes For

Lamins ALamins A

Lack of Specificity of Lack of Specificity of The Dystrophic The Dystrophic

Changes Observed.Changes Observed.

Joint Contractures Joint Contractures Leading To Muscle Leading To Muscle

Weakness and Weakness and Wasting Usually Some Wasting Usually Some Cardiac InvolvementCardiac Involvement

Spinal Muscular Spinal Muscular AtrophyAtrophy

Mutation In The SMN Mutation In The SMN GeneGene

Degeneration of Motor Degeneration of Motor Neurons Which Are Neurons Which Are Nerve Cells In The Nerve Cells In The

Spinal Cord.Spinal Cord.

Poor Muscle Tone, Poor Muscle Tone, Absence of Deep Absence of Deep Tendon Reflexes Tendon Reflexes

3D Images of The Actin Binding 3D Images of The Actin Binding Sight Of DystrophinSight Of Dystrophin

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

Bibliography (Cont.)Bibliography (Cont.) PubMedPubMed

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Multiexon skipping leading to an artificial DMD protein lacking amino acids from exon 45 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.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;