Domiant mutations and rogue proteins Flashcards
Why are dominant mutations so important ? What are rogue proteins?
Dominant mutations- easy to deal with genetically ( however, can be complex on molecular level)
-Dominant mutations have led to the discovery of inherited disease
-Rogue Proteins: proteins that are doing something that they should NOT be doing (in the wrong place, doing the wrong Job)
Discuss the discovery of inherited diseases, including the scientist who observed this.
Discovery of inherited diseases:
-Pierre- Louis Moreau De Maupertis (1698-1759) looked at family records and identified that Polydactyly was clearly INHERITED in the Ruhe family, because it passed from one affected individual to another
- He observed that it could be inherited from either parent
-genetically inherited human disorder
What is Polydactyly?
Polydactyly: An condition in which one is born with extra fingers or toes on a hand or foot
-genetically inherited condition
ex: 6 fingers, or 6 toes
Who was George Huntington and what did he discover? What is a chorea and what were its key features ?
During the 180os, George Huntington identifies a unique chorea
Chorea: set of individuals with movement disorder that became worse and eventually led to death
Key features of Huntingtons’s chorea (Huntington disease)
-“all the symptoms of common chorea (movement disorder ) were only in aggravated degree” (serious medical condition; symptoms start mild and progressively get worse )
-“there was a tendency to insanity, and sometimes that form of insanity which leafs to suicide, is marked” (referring to individuals with chorea, who committed suicide)
-“its third peculiarity is its coming on, at least as a grave disease, only adult life” (Huntington described how the disorder had a Late onset, later in adult life, or as an elderly)
why are fatal diseases found in young children?
Fatal diseases found in young children due to those diseases with Late onset. As you would have already have your own family, and been older before realizing you have Huntington’s disease. Hence, the disease could have already been passed on to child.
how does Huntington’ s disease affect the brain
Explain Huntington’s viewpoint when discussing about chorea being inherited
Huntington’s disease alters brain structure and function
-Huntingtion’s Chorea is inherited:
“when either or both the parents have shown manifestations of the disease, one or more of the offspring almost invariably suffer from the disease, if they live to adult age
-“But by any chance these children go through life without it, the thread is broken” (if children does not have disease, they will not pass it on to their kids)
-“it never skips a generation”
What kind of mutation is Huntington’s disease caused by? what allele causes the disease?
Huntington’s Disease is caused by a DOMINANT MUTATION
dominant allele causes disease (recessive allele is cauisng disease
if one parent is heterozygous for disease, 50% chancre for each child of getting the disease
ex: village in Venezuela has 7 generations of Huntingon’s disease: caused by TOXIC Protein
-Huntington was one of earliest human diseases that were mapped and cloned (it is incurable and fatal)
Discuss the different symbols in pedigree
Pedigree symbols: (intend to rep
square: male
circle: female
children are shown in birth order
Mating: square attached to circle
twins are special:
dizygotic (fraternal twins) : share a single point
has extra line for identical twins (monozygotic)
affected individuals are shaded
dead individuals: line through square or circle
how does Age affect Hungtington’s disease ?
Depending on age, will determine if your children still could have Huntington’s disease or not
For instance, if the mother or father is old (in 50s) with no record of the Disease, the children will most likely not have Huntington’s Disease (since disease is at late onset)
-However if look a genetic pedigree of young mother or father (IN 20s, or 30s,) there is still a chance that the children can have the disease if either parent ends up having it (late onset diseased ) in their 50s- onward
what happens to be people who are homozygous for Huntington trait?
They will have the onset of the disease at an EARLY AGE (if homozygous)
disease- incurable and fatal (whether HH or Hh)
What is the mechanism that causes Huntington’s Disease.
Huntington’s Disease is a CAG EXPANSION Disease
Huntington’s gene encodes a large protein
-At the start of the HD messenger RNA, their are several CAG repeats that encode for GLUTAMINE (string of glutamine)
- patients with Huntington’s Disease tend to have more CAG repeats than those who are normal (however not frame shift mutations, or amino acid changes)
Compare and contrast the number of CAG repeats in normal individuals vs those with Huntington’s Disease
Patients with Huntington’s Disease tend to have more repeats
-Normal Individual- 7-30 CAG repeats
-Huntington’s Disease: More than 30 CAG repeats (encoded more glutamines at start of protein)
Discuss what occurs in the brains of those with Huntington’s disease
People with Huntington’s Disease have a HIGHER number of CAG repeats and the CAG repeats will get BIGGER in the cells of the brain as they get older
Side Note: If DNA polymerase is faced with string gf Identical Nucleotides; it can make a mistake by deleting to adding more nucleotides to strand.
What molecular variation is associated with earlier death in those with Huntington’s Disease?
LONGER REPEATS (more CAGS) are associated with Earlier death in those who have Huntington’s Disease
How large Is the Huntington HTT protein ?
How is the protein affected in those with Huntington’s Disease?
The HTT protein is pretty long with more than 3,000 amino acids
-The Glutamine repeats (CAG) affect one end of the large HTT protein
(but rest of protein functions well)
How are changes in the protein observed? Explain how this process occurs
You can measure the changes in a protein by measuring DNA sizes with agarose gel electrophoresis.
process of Measuring DNA sizes (with gel electrophoresis) :
-DNA is a double helix with deoxyribophosphate backbone. The phosphates has Negative charge. if you put DNA on well, the DNA (with negative charge) gets electrically pulled toward positive electrode and will separate by size
** the SMALLER DNA fragments move FASTER (towards bottom) **
what is the purpose of measuring DNA size with gel electrophoresis? Provide an example
We can use information about DNA size to help us make diagnoses about Huntington’s Disorder
ex: have DNA samples from individuals in a family,
use PCR reaction to AMPLIFY the start of Huntington’s disease and observe
Pedigree example
-parents; Dad was 75 and had 1 fragment; wife had Huntington’s disease, 76 years old and had 2 fragments; Son has Huntington who has 2 fragments like mom and they both have bigger fragment than dad
is one of the sister’s Likely to contract Huntington’s Disease (pedigree shows 3 circles ) ?
Answer; Daughter 47 is likely to have Huntington’s Disease since she has one allele of the gene that is too large (bigger than mom and son with HD) likely due to CAG repeats
What other genes have dominant disorders caused by CAG repeats expansions? Explain the problem with these dominant diseases like Huntington’s Disease that have CAG repeats
Why are these Dominant diseases?
dominant disorders that are also caused by CAG repeat expansions in proteins:
mutation in Ataxin gene (nervous system function), HD, Androgen receptor, Atrophin, and SBMA
when the number of CAG repeats gets too High individual gets dominant disease
Problem in Huntington’s disease :
too many glutamines in proteins, it affects ability to break down or dispose of protein- causes build up of clumps of genes that clog the cell
each dominant disease slowly affects the cells where genes are normally active. The protein is not properly disposed of and the garbage that builds up causes symptoms in the body.
why dominant disease? ;
people with one copy or two copies of gene, still make defective protein that will accumulate and cause problems
-Still no cure for disease
