9 10 Genetic Diseases-Table 1

Question 1

what is incomplete peneterance

Answer 1

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.

Question 2

what is age-dependent penetrance

Answer 2

think of inherited breast and colon cancer or Huntington disease.

Question 3

what is variable expression?

Answer 3

the expression of dominant gene in a widely varied way.

Question 4

what is pleiotrophy

Answer 4

a single disease causing mutations affect mutliple organs or parts of the bodies.

Question 5

what is it called when the eye reflects as white instead of red.

Answer 5

luekocoria

Question 6

what would a leukocoria indicate?

Answer 6

retinoblastoma

Question 7

Describe Retinoblastoma

Answer 7

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.

Question 8

what is unique about the pedigree for a retino blastoma

Answer 8

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.

Question 9

how do we estimate penetrance?

Answer 9

calculate the proportion of obligat carriers who deveop the disease (90%) for retinoblastoma

Question 10

what is the prob. of having retino blastoma with a known carrier parent and a 90% penetrance?

Answer 10

45% (use the multiplicatin rule for probability)

Question 11

what is the difference between the hereditary and non-hereditary presentation of retinoblastoma?

Answer 11

40/60 split with sporadic dominating. Soradic: unilateral, unifocal tumor. Hereditary cases: usually bilateral, multifocal tumors.

Question 12

What is the two hit model?

Answer 12

there must be a “hit” on both of the coppies of the locus (on both of the matching chromosomes) before a cancer will develop

Question 13

why is retinoblastoma such a random event even when the gene for it is inherited?

Answer 13

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.

Question 14

what type of gene fits the two hit model?

Answer 14

these genes are tumor suppressors and the first was RB1

Question 15

what is the fundtion of pRb?

Answer 15

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.

Question 16

how can the cell inactivate pRb?

Answer 16

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.

Question 17

why is Rb so important?

Answer 17

it is found to be mutated in almost all cancers! i.e loss of pRb activity increases cell division and promotes tumor formation.

Question 18

if you have retinoblastoma, you are worried about further cacner forming, why?

Answer 18

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)

Question 19

what are some of the symptoms of Huntington disease?

Answer 19

progressive loss of motor control (chorea); Dementia; Depression, psychosis; 15-year onset.

Question 20

how does huntington disease present autosomal dominant in an unusual way?

Answer 20

it is delayed age of onset. It won’t show up in some cases until very late in life.

Question 21

why might affected fathers that pass on the huntington disease result in children with quicker onset of the disease?

Answer 21

there are more mutations in the germ cells of men and therefore more CAG repeats passed on and the children develop the diseasse faster.

Question 22

what is the genetic cause of Hintington?

Answer 22

CAG repeat number in the first exon (40 or more and you are at risk for huntington disease)

Question 23

what is the range in the number of CAG repeats compared to the development of huntington

Answer 23

less than 26 normal, 27-35 is intermediate (these are both unafected ranges); 36-39 are reduced penetrance; more than 40 are full penetrance.

Question 24

what is the relationship between the number of CAG repeates in the huntington gene and age of onset

Answer 24

inversly related. the more repeates the younger the age of onset

Question 25

what causes huntingtons after the gene is had?

Answer 25

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.

Question 26

what are some developing therapies for huntington?

Answer 26

agenst that prevent the polyglutamin aggregation, and RNA interference (RNAi) blocks expression of mutant HD gene.

Question 27

what is neurofibromin

Answer 27

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!

Question 28

What is the microbilogical cause of neurofibromin?

Answer 28

neurofibromin converts active ras to inactive ras. Therefore if there is mutated neurofibromin gene then Ras is over-expressed. therefore cell growth!

Question 29

what affects variable expression?

Answer 29

environmental variation; Allelic heterogeneity (different mutations at the locus) modifier loci

Question 30

what is marfan syndrome?

Answer 30

Skeletal defects; hyperextensibile joints and arachnodactyly; ocular defects (stabismus where the eyes don’t center together); COPD; Cardiovascular defects (mitral valve prolapse, aortic dilation)

Question 31

what are some physical signs of arachnodactyly

Answer 31

steinberg sign (where thumbs can reach accross the palms and touch); walker-murdoch (wrist sign) where the thumb and pinky can encircle the wrist

Question 32

what cuases marfan?

Answer 32

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.

Question 33

what is a dominant negative effect?

Answer 33

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

Question 34

how do you treat marfan’s syndrome

Answer 34

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.