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UW-Madison ANSCI 361 - Muscular Dystrophy in Golden Retriever Dogs

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An Sci 361 1st Edition Lecture 4 Outline of Last Lecture I. Learning Goalsa. BLADb. CLADII. BLADa. Causeb. Prevalencec. Who is responsible?III. CLADIV. DUMPSa. DetectionOutline of Current Lecture I. Learning Goalsa. Dystrophinb. RingoII. Duchenne Muscular Dystrophy (DMD)III. Muscular Dystrophy in Golden Retrieversa. Dystrophinb. RNA Splicingc. Causesd. TreatmentsIV. Exon Skipping TherapyV. Stem Cell InjectionsCurrent LectureLearning Goals:Understand dystrophin structure and causative mutation including – splicing and alternative splicing– Mutations causing MDMolecular treatmentStem cell treatmentThese notes represent a detailed interpretation of the professor’s lecture. GradeBuddy is best used as a supplement to your own notes, not as a substitute.Ringo: phenotype-genotype connection• Types of human muscular dystrophy• Becker’s muscular dystrophy (BMD) • Duchenne muscular dystrophy (DMD)Duchenne Muscular Dystrophy (DMD):• Dystrophin is the gene responsible for DMD • A recessive, fatal, X-linked disorder occurring at a frequency of about 1 in 3,500 new-born males. • Boys usually lose the ability to walk by age 12, and generally don't survive beyond their 20s.• DMD patients carry mutations which cause premature translation termination (nonsenseor frame shift mutations)• Types of muscular dystrophy in dogs• canine X-Linked muscular dystrophy (CXMD) • Becker’s muscular dystrophy (BMD) • autosomal recessive muscular dystrophy (ARMD)Muscular Dystrophy in Golden Retrievers: The dog is able to chew but drops food during swallowing Muscle stiffness Pneumonia Cardiac failure Enlargement of the tongue (hypertrophy) Large variation in disease phenotype (Why?)Dystrophin:• Dystrophin maps to chromosome X• The gene spans 2.4 million base pairs of genomic DNA (79 exons). • 14 Kb transcript , under the control of multiple promoters• The main protein product: 3,685 amino acids.• Dystrophin is needed for the mechanical stability of the muscle cells.RNA Splicing:The original mRNA is a copy of all exons and introns of the geneRNA splicing: before the RNA moves from the nucleus to the cytoplasm, the introns are removed and the exons are spliced together Causes of Muscular Dystrophy:• Many mutations in introns have no effect on gene function• Some sequences in the introns are essential• GT-AG rule: introns begin with a GT and end with an AG. – mutation near either end of intron may cause a change in splicing of exons and produce abnormal proteinFrameshift mutation produces a STOP codon in exon 8 of dystrophin in Golden Retrievers Base substitution in the 3` splice-acceptor site of intron 6 of the dystrophin gene (AG to GG) Exon 7 is spliced along with intron 6 and intron 7 Deletion of exon 7 introduces a stop codon in exon 8 Result: truncated transcript of dystrophinTreatment-Molecular: gene therapy; gene correction-Cellular: stem cell transplanted into diseased muscle-Pharmacologic: compounds that reduce inflammation or muscle massExon 51 can not join up with exon 53, which prevents the rest of the exons being assembled.Exon Skipping Therapy:Normal splice motifs are targeted to mask the exon from the splicing machinery, leading to exclusion of the exon from the mRNA.Small pieces of DNA called antisense oligonucleotides (AOs) or 'molecular patches' are used to mask the exon that you want to skip, so that it is ignored during protein production. Golden retriever dog is the only animal model “developing progressive, fatal disease strikingly similar to the human condition”Single mutation in intron 6 leads to:Complete absence of the dystrophin proteinEarly and severe muscle degeneration with nearly complete loss of motility and walking ability.Death usually occurs at about 1 year of age as a result of failure of respiratory muscles.Stem Cell Injections:Four dogs received autologous stem cellsSix dogs received wild-type stem cells from a donorThree dystrophic dogs were not treated (controls)Intra-arterial delivery of wild-type canine mesoangioblasts (vessel-associated stem cells) results in an extensive recovery of dystrophin expression, normal muscle morphology and


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