Marfan Syndrome, Cystic Fibrosis, and Alzheimer Disease Flashcards
Which of the following is not a characteristic of Marfan Syndrome Patients:
Skeletal: Tall and thin, long extremities, scoliosis, kyphosis, long and narrow face with deep set eyes, joint laxity.
Ocular: ectopia lentis (down and out), myopia, and diplopia
Dural ectasia
Cardio: dilation of aorta, mitral valve prolapse
Kyphosis, the ectopia lentis is actually upward and inward, no diplopia
What mode of transmission does the Marfan mutation show?
Autosomal dominant
What is the mutation in Marfan and what problem does it cause?
FBN1 gene- encodes fibrillin, an extracellular matrix protein that contrubutes to microfibril formation (structural). **It (microfibrils) negatively regulates TGFB by binding/”soaking” it up. So there’s too much TGFB signalling in Marfan Syndrome.
Marfan Syndrome shows all of the following except: Pleiotropy Allelic heterogeneity Locus heterogeneity Haploinsufficiency Dominant negative mutations Variable expressivity Incomplete penetrance
No locus heterogeneity, only the FBN1 gene is affected.
Also, it is fully penetrant.
What evidence is there that a missense mutation in the FBN1 gene causes a dominant negative mutant?
Missense mutations reduce fibrillin to <35% of wt; you would expect to see a reduction of 50% if it was not a dominant negative muation.
What percent of Marfan cases are from a new mutation?
25-30%
What is the treatment for Marfan?
Managing symptoms. Eg. if aortic defect present, surgically correct it. Has improved life expectancy.
Clinical trial: Losartan- TGFB inhibitor
Name two other mutations with similar symptoms to Marfan, and mention how they differ from Marfan.
Homocysteineuria- elevated homocysteine (from Met) interferes with collagen cross-linking.
Differences: Autosomal recessive; ectopia lentis is lateral; thromboembolisms common; mental retardation.
Loeys-Dietz Syndrome- mutation in TGFBR1 or 2.
Differences: GoF mutation; aortic aneurysms tend to rupture at smaller diameters.
Some FBN1 mutations do not cause Marfan, but can produce these three problems:
1) MASS (mitral valve prolapse, aortic enlargement, skin and skeletal disorders)
2) Mitral valve prolapse syndrome
3) Familial ectopia lentis
True or false: CF is the most common autosomal dominant disorder in white children, but it is also common in blacks and asians.
False: it is autosomal recessive, and it is not common in blacks and asians.
What is the carrier frequency of CF? What percent of the CF alleles are in homozygotes/heterozygotes?
1/25
2%/98%
Which of the following are not symptoms of CF?
Rhinitis, Sinusitis, and Obstructive Lung Disease
Pancreatic insufficiency–> GI absorption defects–> poor growth
Meconium ileus in 10-20%
Congenital bilateral absense of vas deferens (CBAVD) (infertile, but not sterile)
Reduced female fertility
Elevated salt in sweat
All are symptoms
True or False: to make the diagnosis of CF, the patient must have at least one symptom (including positive family history), and evidence of CFTR dysfunction.
True
CFTR dysfunction:
sweat Cl- conc. >60mEq/L
known mutation
abnormal ion transport across nasal epithelilum
What does the CFTR gene encode?
Large integral membrane protein in the ABC (Atp Binding Cassette) transporter protein class, which produce ATP-regulated chloride channels and regulates other ion channels.
What is the most common CFTR gene mutation and what does it do?
DeltaF508 mutation, which deletes Phe in the Nucleotide (ATP) Binding Domain (NBD)– **It impairs protein exit from endoplasmic reticulum
What is the second most common CFTR gene mutation?
Decrease in the number of T’s (9, 7, 5) in intron 8–> less efficient splicing and produces a protein lacking exon 9 (dN produce CF phenotype though?)
