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Huntington's Disease.docx

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Bhagwati Gupta

November 18 , 2013 Biology 2C03: Genetics Huntington’s Disease Case Study: Dominant Disorders - Triple-repeat disorder, Huntington’s disease - Huntington’s disease: mapping the Huntington gene - Disease caused by tri-nucleotide repeats - Several human disorders caused by tri-nucleotide repeats - Normal range refers to the number of copies in normal individuals = no risk for the disease - Susceptibility increases with number of copies of repeats Huntington’s Disease was Described in 1893 by Wiliam Osler - A hereditary form of chorea = the inability to control one’s muslces - This is a progressive disorder that gradually worsens = loss of control of the arms, legs, and facial muscles is associated with bizarre, sudden, and random movements. Symptoms did not manifest until the age of 40 or 50 - The first report from George Huntington in 1872 - Observations of families on Long Island showed characteristics of a dominant disorder in which every generation may be affected…but this predated the work of Mendel - Age dependent disorder: more likely to exhibit at later stages, but does happen in earlier stages of life - Neuronal disorders are degeneration, it takes a long time for a large group of neurons to die and for the disease to appear - Charles Davenport in 1916 studied this inheritance pattern in detail – looking at 962 patients on Long Island…only five were not clearly the children of affected parents - Haplotype segregation in American family - Find frequency of haplotype, and correlated to how many times the haplotype is associated with a diseased individual - Haplotype A:13/18, B: 3/7, C: 1/3, D: ½ - haplotype A is associated with this disease in this American fmaily - Does not skip generations and is therefore dominant disease - 1932, an extensive pedigree analysis was conducted by scientist named Vessie: about 1000 patients on the East coast of America - nearly all were descended from a few individuals from a single village in Suffolk, England who immigrated to America in 1630 - further studies connected other affected families to the same pedigree – had this mutation occurred only once and been passed through generations? - Evidence of new mutations was to appear Clinical Description of the Disease - Wide range of onset (age 2 to 90 reported), but typically appears in the late 40’s and 50’s - Complete penetrance – if an individual carries the mutation, they will eventually show the symptoms - Degenerative disorder that takes about 15 years before eventually leading to death - Transitional phase  Loss of fine motor control, slurring of speech  Nearly constant involuntary movements (chorea) - Advanced phase: loss of the ability to walk, speech becomes incomprehensible, patients can no longer swallow, memory becomes impaired - Average age of death is 60…due to infection or pneumonia - Environmental factors and genetics - Different sets of mutations; genetic susceptibilities that predispose to different diseases Molecular Basis of Huntington’s Disease - 1978: Nancy Wexler attempts to identify the affected gene in collaboration with James Gusella at Massachusetts General Hospital - Did not have the same resources as we do today to identify the genes responsible for disorders - Looked for a linkage betweena DNA marker and the disease allele i.e. a marker present in the affected individuals, but not in the unaffected - Population: lake Maracaibo in Venezuela - Extended kindred number >14 000 individuals  Mapped pedigrees  Performed neurological assays  Obtained DNA samples and looked for linkage disequilibrium between DNA probes and disease symptoms - A hole lot of luck…8 probe tested whoed linkage - Disease allele mapped to the short arm of chromosome 4 (4p16.3) - Sequenced human DNA, broke into smaller chunks, put into vectors/bacteria to clone and numbered - Smaller DNA chunks used as probes to identify genes responsible for Huntington’s disease - Hybridizing on chromosome 4 - Family studies show that the Huntington’s disease gene is linked to a polymorphic DNA marker that maps to human chromosome 4. The chromosomal localization of the Huntington’s disease gene is the first step in using recombinant DNA technology to identify the primary genetic defect in this disorder Venezuelan Pedigree - Haplotype segregation in Venezualean family is mostly C Molecular Analysis - Marker: 4.9kb fragment (haplotype B) - Linked to disease phenotype - Haplotype: a segment of a chromosome that is defined by a group of molecular markers (SNPs); a group of alleles for these markers are linked and inherited together b an organism form a single parent - Restriction enzyme cuts at different locations - R = restriction enzyme EcoR1 - Found several other EcoR1 - DNA piece can be digested by HindIII - Few EcoR1 and HindIII sites - Take corresponding region of chromosome and digested with HindIII to find digestive pattern - Probe 8 is mapping on the chromosome 4 - Conserved locations (always cut by HindIII) - Two other HindIII sites are variable (are polymorphic) due to SNP SNPs – disrupt HINDIII restrictive enzyme - Results in different sizes of DNA fragments - If a polymorphic site was missing, that piece will not be cut, and you get a combined kb - Results in four different haplotypes  + represents present site/- represents absent site  A: first polymorphic is missed, second is present  B: both polymorphic sites absent  C: both polymorphic sites present  D: first site is present, second site is missing  Because of these two sites you can have four types of haplotypes that will arise November 19 , 2013 Huntington’s Disease Collaborative Research Group (HDCRG) - 10 years to identify the HD gene - Gene IT25: protein coding gene (transcribed into a mRNA) - Identified a region of the gene that contained a repeated DNA element consisting of three nucleotides, CAG, repeated 21 times near the beginning of the gene (MacDonald et al., 1993) - Non-HD controls, the number of CAG repeats varied from six to 35; they described this phenomenon as instability of the trinucleotide repeat - Individuals with HD, 40 or more CAG repeats (largest number of CAG repeats the researchers detected was 100) - The researchers thus concluded that the trinucleotide repeat expansion in the IT15 gene was responsible for HD, and IT15 is now called HTT (huntingtin) - The more repeats, the earlier the onset and increased rate of progression, but the number of repeats does not correlate with increased overall severity CAG Repeat is in the Protein Coding Portion of the Gene - This creates an unusual string of glutamines (codon CAG) in the protein = polyglutamine tract (or polyQ tract) - Since this is a dominant disorder, this seems to result in a gain of function phenotype rather than a loss of function – not an absence of the gene but an abnormally high number of glutamine coding genes that causes the disease - What does the Huntington protein do? - How does a string of glutamines affect this function? - When this protein with a large glutamine folds, it forms aggregates in neurons and cannot be utilized - Cell death of medium-sized spiny neurons in the striatum of the brain - Striatum: planning and modulation of movement pathways; also involved in a variety of other cognitive processes - Normal function of Huntington protein is unknown - Effect of glutamine repeats is unknown The Function of Htt in Humans is Unclear - Htt interacts with proteins which are involved in transcription, cell singaling and intracellular transporting - In animals genetically modified to exhibit HD, several functions of Htt have been found:  An anti-apoptotic agent preventing programmed cell death and
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