FTM 67 - Molecular Mechanisms in Inherited Diseases

Question 1

Describe the basic strucutre and function of the CFTR.

Answer 1

Question 2

What is the most common cause of mortality and morbitidy in CF patients? What causes this?

Answer 2

Question 3

Describe how CF affects the pancreas and what this leads to.

Answer 3

CF causes exocrine pancreatic insufficiency by causing thicker secretions to accumulate and obstruce the duct lumen leading to tissue destruction. Fibrotic tissue and fat gradually replace the pancreatic parenchyma - hence the name CF. This leads to maldigestion of nutrients and excretion of fat in the stool (steatorrhea). This leads to protein malnutrition and delay in growth of children

Question 4

Besides the lungs, pancreas, and skin, what other systems are affected by CF and how?

Answer 4

Due to the viscid secretions in the intestine, some childrem will develop meconium ileus (small intestine blockage by meconium) and other intestinal obstructions.

Most males with CF are infertile because they lack a vas deferens, a phenotype known as congenital bilateral absence of the vas deferens (CBAVD).

Question 5

Describe the most common CFTR mutation and how it affects the CFTR.

Answer 5

It is a 3-bp deletion on the long arm of chromosome 7 that eliminates the phenylalanine residue of CFTR at 508. Known as the ΔF508 mutation. This mutation prevents the CFTR from maturing properly and reaching the PM.

Question 6

What are the tests used to diagnose CF?

Answer 6

Sweat Test

ASO test

Allele specific PCR

Question 7

Describe the mutation that causes Sickle Cell Anemia and how it affects the ß-globin protein.

Answer 7

A missense point mutation in the ß-globin gene causes a glutamic acid (hydrophilic) to be replaced by a valine (hydrophobic). This results in the formation of a hydrophobic pocket on the exterior of the hemoglobin molecule. As a result, deoxygenated hemoglobin tends to aggregate to form long filamentous like structures that distorts the RBC into a sickle shape

Question 8

Why does the sickle shape of RBCs lead to anemia? What else does this cause?

Answer 8

Question 9

Describe how protein electrophoresis can be used to diagnose sickle cell anemia.

Answer 9

Question 10

Describe how a dot blot test can be used to diagnose Sickle Cell Anemia

Answer 10

Question 11

Describe how RFLP analysis can be used to diagnose sickle cell anemia.

Answer 11

Question 12

Facts to know about DMD

Answer 12

Question 13

Facts to know about BMD.

Answer 13

Question 14

Compare and contrast DMD with BMD

Answer 14

• Both due to mutations of dystrophin gene
• DMD is more severe than BMD
• DMD is from an almost complete absence of functional dystrophin while BMD is is due to production of abnormal dystrophin or less dystrophin
• Almost all DMD deletions involve a frameshift mutation or a large deletion of exons. BMD deletions are in-frame

Question 15

How can PCR be used to distinguish DMD from BMD?

Answer 15

Question 16

What are some of the clinical features of DMD?

Answer 16

• Weakness of pectoral muscles, trunk, and upper & lower legs leading to difficulty in rising, climbing stairs and maintaining balance
• Boys with DMD rise of the floor using the Gower’s maneuver, getting on the hands and knees, elevating posterior, walking hands up the legs
• Pseudohypertrophy of calves due to the replacement of muscle tissue with connective tissue and fat.

Question 17

Facts to know about the dystrophin gene

Answer 17

• Located on X-chromosome
• Largest gene in the body
• Expressed mainly in smooth, cardiac, and skeletal muscle, with lower levels in the brain

Question 18

What are the primary functions of the dystrophin protein?

Answer 18

Question 19

What does histological staining of muscle cells in individuals with muscular dystrophy reveal?

Answer 19

An increase in connective tissue between myocytes

Question 20

How can a western blot be used to distinguis between BMD and DMD?

Answer 20

Question 21

What blood test can be ran to detect muscular dystrophy?

Answer 21

Question 22

How can a female heterozygous for muscular dystrophy mutations have clinical expression of the disease?

Answer 22

Asymmetric X-inactivation