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Unformatted text preview: Understand the concept of stable and unstable mutations Understand expressivity of mutations and basis for disease Describe how diseases can be caused by the expansion of simple DNA repeats Vocab repeat, anticipation, fragile site, expansion, genetic instability, gain- of-function, loss-of-function Outline- Overview of repeats, diseases, classification - Fragile X syndrome = example of loss-of-function repeat disease- Huntingtons disease = example of protein gain-of- function repeat disease a) four aspects of CAG polyglutamine diseases - Myotonic dystrophy and the other RNA gain-of-function repeat diseases- Summary slides for three different disease types- Repeat expansion disease o Fragile X syndrome of mental retardation o FRAXE mental retardation o X-linked spinal and bulbar muscular atrophy o Myotonic dystrophy 1 and 2 o Huntingtons disease 1 and 2 o Dentatorubral pallidoluysian atrophy o Friedreichs ataxia o Oculopharyngeal muscular dystrophy o Myoclonic epilepsy of unverricht-Lundborg o Spinocerebellar ataxia types 1, 2, 3, 6, 7,8, 10, 12, 17- Disease repeats vary in sequence composition and length o Most are trinucleotides; however, tetranucleotides, pentanucletodies, and 12-mer repeats also o 2 nt 13 nt in length = microsatellites o littered throughout the human genome, and initially felt to be of no functional significance; were studied for years as an evolutionary curiosity o Discovery of repeat expansions as a cause of human genetic diseases (molecular genetic mutation) In addition to gross rearrangements (deletion; inversions) Minor alterations (substitutions; point mutation; frameshift)- Disease-causing repeats are expanded, and form a separate, non- overlapping distribution- Sequence composition AND location within gene predict mechanism of disease mutation and so permit classification o Location ? -- promoter, origin or replication, etc- Four types of repeat diseases o Loss of function repeat diseases o CAG / polyglutamine repeat diseases o RNA gain-of-function repeat dieases o Polyalanine repeat diseases- Loss of function repeat disease fragile X syndrome of mental retardation o Most common hereditary form o Mild physical phenotype not really dysmorphic o A cytogenetic abnormality, the fragile X chromosome is sometimes seen o Unusual X linked pattern of inheritance = the so called Sherman paradox o CGG repeats o Normal 6-50; permutation 52-200; disease 200 to greater than 1000 o The number of repeats increases mutation (repeat expansion) o Molecular basis Expansion of the CGG repeat leads to decreased mRNA levels and decreased levels of the FMR-1 protein Most affected individuals make no FMR-1 protein Point mutations in the FMR-1 RNA binding domain and deletions of the FMR-1 gene can also cause fragile X syndrome (this is rare) LOSS-of-FUNCTION of the FMR-1 protein Understand the concept of stable and unstable mutations Understand expressivity of mutations and basis for disease Describe how diseases can be caused...
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- Spring '11