Marfan, Cystic Fibrosis, Alzheimers

Question 1

What is the phenotype for Marfan syndrome?

Answer 1

joint laxity, scoliosis, myopia, dural ectasia (lumbosacral stretching of dural sac), mitral valve prolapse

Question 2

What is the gene involved in Marfan syndrome?

Answer 2

mutant FBN1 gene encodes fibrillin and increases TGF Beta expression

Question 3

What is the pattern of heredity for Marfan Syndrome?

Answer 3

autosomal dominant

Question 4

Are most of Marfan cases null or dominant negative?

Answer 4

Most cases are dominant negative with non-functional fibrillin unable to inhibit TGF Beta; null mutation is one copy knocked out with elevated TGF Beta

Question 5

Marfan syndrome shoes what genetic characteristics?

Answer 5

pleiotropy, variable expressivity though fully penetrant, and allelic heterogeneity (a quarter are new mutations)

Question 6

What is in clinical trial to treat Marfan’s?

Answer 6

Losartan - angiotensin receptor blocker (TGF Beta inhibitor)

Question 7

What is the phenotype of homocystinuria?

Answer 7

interferes with collagen cross-linking –> autosomal recessive, similar to Marfan’s but with mental retardation

Question 8

What is Loeys-Dietz Syndrome?

Answer 8

Very similar to Margans with mutation in TGF Beta Receptor

Question 9

What other dieases can FBN1 mutations produce outside Marfan

Answer 9

1. MASS: mitral valve prolapse, aortic enlargement, skin, and skeletal disorder
2. Mitral valve prolapse syndrome
3. Familial ectopia lentis

Question 10

How do you treat cystic fibrosis?

Answer 10

oral pancreatic enzymes, oral antibiotics effective against H. Influenza and Staph

Question 11

What is the phenotype for Cystic Fibrosis?

Answer 11

recurrent lung infection, meconium ileus, CBAVD (congenital bilateral absence of vas deferens)

Question 12

What is the gene involved with Cystic Fibrosis?

Answer 12

CFTR, an integral transmembrane protein/ATP binding cassette, maintains hydration of secretions in airways and ducts

Question 13

What happens when CFTR protein non-functioning?

Answer 13

NaCl pulls water into the lumen, but when CFTR not working, Na+ increases inside the cell and secretions become viscous

Question 14

What is the mutation in cystic fibrosis?

Answer 14

Deletion of Phe at position 508 in CFTR, impairs protein exit from endoplasmic reticulum. Causes less efficient splicing, leading to protein lacking exon 9. No change in reading frame.

Question 15

What is CBAVD?

Answer 15

Congenital bilateral absence of vas deferens, most have mutations in CFTR but don’t develop pulmonary symptoms.

Question 16

What is treatment for Cystic Fibrosis?

Answer 16

Dornase alpha: DNAse that reduces viscosity of fluid in lungs

Question 17

What does a mutation in in SCNN1 cause?

Answer 17

encodes a sodium channel, can cause cystic fibrosis-like symptoms.

Question 18

What is the mechanism of Alzheimers?

Answer 18

amyloid plaques and neurofibrillary tangles in cerebral cortex and hippocampus. Death 8 - 10 years

Question 19

What are the early, middle, late symptoms of Alzheimer disease?

Answer 19

Early - short term memory loss
Middle - needs assistance with complex tasks
Late - muscle deterioration, inability to feed self, etc.

Question 20

What protein protein is overproduced in Alzheimers?

Answer 20

AB 42 is cleaved from BAPP (beta amyloid precursor protein).

Question 21

What prevents formation of AB 42?

Answer 21

Alpha secretase

Question 22

What promotes formation of AB 42?

Answer 22

Beta (AB 40) and gamma secretase (AB 42)

Question 23

What is AB 42?

Answer 23

neurotoxic protein, accumulates in extracellular amyloid plaques.

Question 24

What are tau tangles?

Answer 24

Tau protein normally promotes stability of microtubules but in Alzheimers, Tau protein is hyperphosphprylated leading to tangles that accumulate intracellularly.

Question 25

What promotes development of Alzheimer disease?

Answer 25

e4 allele of APOE increases risk 10-30x. mechanism unclear.

Question 26

Mutations in what 3 genes increase risk of AD, early onset AD?

Answer 26

BAPP on Chromosome 21
Presenillin1 on Chromosome 14, fully penetrant
Presenillin 2 on chomosome 1, incomplele penetrance

Question 27

Prevention of AD?

Answer 27

Mediterranean diet, intellectual activity, ginkgo