9 10 Genetic Diseases-Table 1 Flashcards
what is incomplete peneterance
there is a diminished probability of having the phenotype despite the fact that the genotype is present. i.e. some with the dominant gene don’t get the disease.
what is age-dependent penetrance
think of inherited breast and colon cancer or Huntington disease.
what is variable expression?
the expression of dominant gene in a widely varied way.
what is pleiotrophy
a single disease causing mutations affect mutliple organs or parts of the bodies.
what is it called when the eye reflects as white instead of red.
luekocoria
what would a leukocoria indicate?
retinoblastoma
Describe Retinoblastoma
cancer of the eye, it is autosomal dominant with incomplete penetrance, 1/20,000 children, 5% of childhood blindness, most common eye tumor for children, almost always onset before six years of age.
what is unique about the pedigree for a retino blastoma
it is a dominant disorder, but can exhibit obligate carriers (one who must have the genotype) but never develops the phenotype! i.e. incomplete penetrance.
how do we estimate penetrance?
calculate the proportion of obligat carriers who deveop the disease (90%) for retinoblastoma
what is the prob. of having retino blastoma with a known carrier parent and a 90% penetrance?
45% (use the multiplicatin rule for probability)
what is the difference between the hereditary and non-hereditary presentation of retinoblastoma?
40/60 split with sporadic dominating. Soradic: unilateral, unifocal tumor. Hereditary cases: usually bilateral, multifocal tumors.
What is the two hit model?
there must be a “hit” on both of the coppies of the locus (on both of the matching chromosomes) before a cancer will develop
why is retinoblastoma such a random event even when the gene for it is inherited?
because there is a need for a second hit or a spontaneious mutaiton even for those that carry the mutation on one of the coppies of the genes.
what type of gene fits the two hit model?
these genes are tumor suppressors and the first was RB1
what is the fundtion of pRb?
pRb is a “brake” on E2F which is a promotor for cell replication. CDK4 de-activates pRb and cyclin D would activate CDK4: therefore activate CDK4 and de-activate pRB and allow E2F to promote cell division.
how can the cell inactivate pRb?
phosphorylation by cyclin dependent kinases (CDK4) (normal); loss of function mutation of both copies of rB1 or by papilloma virus E7 oncoprotein in cervical cancer cases.
why is Rb so important?
it is found to be mutated in almost all cancers! i.e loss of pRb activity increases cell division and promotes tumor formation.
if you have retinoblastoma, you are worried about further cacner forming, why?
because the “hit” on pRb is in all of the cells of someone who inherieted the pRb mutation so they are at risk of getting a second “hit” in other cells (esp. in bone cancer)
what are some of the symptoms of Huntington disease?
progressive loss of motor control (chorea); Dementia; Depression, psychosis; 15-year onset.
how does huntington disease present autosomal dominant in an unusual way?
it is delayed age of onset. It won’t show up in some cases until very late in life.
why might affected fathers that pass on the huntington disease result in children with quicker onset of the disease?
there are more mutations in the germ cells of men and therefore more CAG repeats passed on and the children develop the diseasse faster.
what is the genetic cause of Hintington?
CAG repeat number in the first exon (40 or more and you are at risk for huntington disease)
what is the range in the number of CAG repeats compared to the development of huntington
less than 26 normal, 27-35 is intermediate (these are both unafected ranges); 36-39 are reduced penetrance; more than 40 are full penetrance.
what is the relationship between the number of CAG repeates in the huntington gene and age of onset
inversly related. the more repeates the younger the age of onset
what causes huntingtons after the gene is had?
polyglutamine aggregation in the cell. (it is a gain in function mutation). This leads to poly ubiquitinaion and to break down by a proteasome. Also implicated is brain-derived neurotrophic factor (BDnF) mutations that will cause aggregates and breakdown trafficking and cell signalling in a neuron.
what are some developing therapies for huntington?
agenst that prevent the polyglutamin aggregation, and RNA interference (RNAi) blocks expression of mutant HD gene.
what is neurofibromin
it is a disease of the nerve sheaths that can present as simply cafe a lait spots or as small neurofibromatosis or as numerous ones oor as lisch nodules (in the eyes) or as large plexiform tumors. It has varied expression!
What is the microbilogical cause of neurofibromin?
neurofibromin converts active ras to inactive ras. Therefore if there is mutated neurofibromin gene then Ras is over-expressed. therefore cell growth!
what affects variable expression?
environmental variation; Allelic heterogeneity (different mutations at the locus) modifier loci
what is marfan syndrome?
Skeletal defects; hyperextensibile joints and arachnodactyly; ocular defects (stabismus where the eyes don’t center together); COPD; Cardiovascular defects (mitral valve prolapse, aortic dilation)
what are some physical signs of arachnodactyly
steinberg sign (where thumbs can reach accross the palms and touch); walker-murdoch (wrist sign) where the thumb and pinky can encircle the wrist
what cuases marfan?
fibrillin gene (most cases), expressed in: suspensory ligament of the eye; periosteum; aorta! this leads to very stretchy fibers. Also fibrillin is a molecular sponge for TFGbeta, therefore a mutation in fibrillin will allow an over expression of TFGbeta.
what is a dominant negative effect?
the one mutated form of the protein overides the normal function of the normal gene: in fibrilin the bad fibers polymerize with the good and poison the fibers
how do you treat marfan’s syndrome
Losartan reduces dilation of the aortic valve by binding to the TGFbeta and effectively doing the job of fibrilin as far as TGFbeta absorption and binding.
