ALL THE SICK THINGS

Question 1

What are the 2 disease associated with the cell membrane?

Answer 1

Acanthocytosis and Hereditary spherocytosis

Question 2

What is another name for acanthocytosis?

Answer 2

Spur Cell Anemia

Question 3

In acanthocytosis, where is the defect seen specifically? What cellular component

Answer 3

RBC cell membrane

Question 4

What is the mode of inheritance for Spur Cell Anemia?

Answer 4

Acquired

Question 5

In acanthocytosis, what causes haemolytic anemia?

Answer 5

excess cholesterol transferred to outer leaflet creates flat, scalloped cells with projections (spur cells), which increase SA of outer bilayer making cells less deformable;

Question 6

The spur cells created in acanthocytosis are sequestered where for destruction?

Answer 6

the spleen

Question 7

What is acanthocytosis commonly associated with?

Answer 7

associated with chronic liver disease or alcohol liver disease

Question 8

What are some common characteristics of acanthocytosis/Spur Cell Anemia?

Answer 8

ascites, jaundiced, caput medusae

Question 9

Where is the defect seen in Hereditary spherocytosis?

Answer 9

RBC cytoskeletal membrane defect due to nonfunctional skeletal protein

Question 10

Which skeletal protein is commonly nonfunctional in hereditary spherocytosis? BONUS: What are the other ones that can also be nonfunctional?

Answer 10

Spectrin most commonly

also ankyrin, or protein 4.1

Question 11

What is the mode of inheritance for hereditary spherocytosis?

Answer 11

75% of cases are Autosomal Dominant

Question 12

How is haemolytic anemia caused in hereditary spherocytosis?

Answer 12

spectrin deficiency causing unstable membrane

membrane loses fragments and becomes less deformable

Question 13

As a result of membrane instability and decreased deformability, what is the most likely fate of the RBC’s affected by hereditary spherocytosis?

Answer 13

increased likely hood of being sequestered to the spleen for destruction

Question 14

What are some common characteristics seen in patients with hereditary spherocytosis?

Answer 14

splenomegaly, jaundice, gallstones

Question 15

How many diseases have we covered in class that deal with the Nucleus?

Answer 15

5

Question 16

What are the diseases that deal with the Nucleus?

Answer 16

Emery-Dreifuss Muscular Dystrophy

Dilated Cardiomyopathy

Lipidodystrophy

Hutchinson-Gilford Progeria Syndrome

Spinal Muscular Dystrophy (SMA) (Type I,II,III - infantile, intermediate, adult)

Question 17

Where is the mutation commonly seen in Emery-Dreifuss? Where else can the mutation be seen?

Answer 17

mutation in Emerin is most common

but also rarely in Lamin A/C

Question 18

Where is the defect seen in Emery-Dreifuss?

Answer 18

defected nuclear envelope

Question 19

What is the mode of inheritance of Emery-Dreifuss if the mutation is seen in Emerin?

Answer 19

X-Linked

Question 20

What is the mode of inheritance of Emery-Dreifuss if the mutation is seen in Lamin A/C?

Answer 20

Autosomal Dominant/Recessive

Question 21

What is the mechanism of the defect caused in Emery-Dreifuss?

Answer 21

defect in lamin assembly/attachment to nuclear envelope causes fragile nuclear envelope resulting in disruption of nuclear function

Question 22

How is chromosome distribution altered in Emery-Dreifuss?

Answer 22

commonly see aberrant distribution of chromosomes

Question 23

What are some common characteristics of Emery-Dreifuss?

Answer 23

contractures in elbows, ankles, neck

muscle weakness, atrophy, heart conduction defects, arrythmias, sudden heart failure

Question 24

For Dilated Cardiomyopathy, where is the defect seen in the nucleus?

Answer 24

Lamin A/C defect (RARE CAUSE FOR THIS AILMENT)

Question 25

What is the mechanism for Dilated Cardiomyopathy associated with nuclear defects?

Answer 25

defected lamin causes fragile nuclear lamina and subsequent cell death

Question 26

What is a common characteristic of Dilated Cardiomyopathy associated with nuclear defects?

Answer 26

CHF

Question 27

Where is the defect commonly seen in Lipodystrophy?

Answer 27

Lamin A/C defect

Question 28

What is the mechanism seen with Lipodystrophy?

Answer 28

preLamin A interacts with adipocyte transcription factors (KNOW THIS! ITS A HUGE DAMN HINT :]) as a result you have impaired adipocyte differentiation

Question 29

What are the common characteristics of Lipodystrophy?

Answer 29

accumulation of adipose tissue in face and neck, peripheral lipoatrophy with muscle prominence

Question 30

Where is the defect seen in Hutchinson-Gilford Progeria Syndrome?

Answer 30

Lamin A defect

Question 31

What is the mode of inheritance of HG-progeria?

Answer 31

Autosomal Dominant (sporadic)

Question 32

What is the mechanism of the defect associated with HG-progeria?

Answer 32

defect in lamin causes fragile nuclear envelope resulting in progressive nuclear damage and premature cell death

Question 33

With HG-progeria, the defect in lamin causes the nuclear envelope to become fragile. As a result, what characteristically forms, what is lost, and what clusters?

Answer 33

bleb formation (SUPER HUGE HINT IN QUESTIONS) loss of peripheral heterochromatin NPC clustering (nuclear pore complex)

Question 34

What are some common characteristics of patients with HG-progeria?

Answer 34

normal at birth/early infancy but failure to thrive around 18-24 months prominent eyes, alopecia, loss of subcutaneous fat, joint stiffness, arteriosclerosis by ~5 yo

Question 35

80% of HG-progeria affected individuals die from what?

Answer 35

myocardial infarction (MI) or CHF

Question 36

Where is the defect seen in Spinal Muscular Atrophy (SMA)?

Answer 36

mutatin of survival of motor neuron protein (SMN) in Gem of nucleus

Question 37

What is the mode of inheritance for SMA?

Answer 37

Recessive

Question 38

What is the mechanism of the defect seen in SMA?

Answer 38

mutated SMN causes defective snRNP assembly leading to subsequent defective pre-mRNA splicing causing loss of motor neurons

Question 39

What are the characteristics seen in individuals with SMA?

Answer 39

sudden onset, rapid progression, muscle weakness & atrophy, hypotonia, dysphagia/feeding difficulties, respiratory tract infections (RTIs)

Question 40

How many diseases have we studied that deal with defects in the Rough ER and Golgi?

Answer 40

3

Question 41

What are the diseases associated with RER and Golgi that we studied so far?

Answer 41

Cystic Fibrosis Familial Hypercholesterolemia I-Cell Disease (KNOW THIS!)

Question 42

Where is the defect seen in Cystic Fibrosis?

Answer 42

protein folding defect defective transport from RER to Golgi

Question 43

What gene is mutated in Cystic Fibrosis? Where is the deletion and what is specifically effected?

Answer 43

CFTR gene single amino acid deletion of F508 within the gene (Phenylalanine) Cl- ion channel effected

Question 44

What is the mode of inheritance for Cystic Fibrosis?

Answer 44

Autosomal recessive

Question 45

What is the mechanism for the defect seen in Cystic Fibrosis?

Answer 45

CFTR is misfolded in the ER so it keeps getting ejected back to cytosol to be degraded via proteasomes

Question 46

What are some common characteristics seen in individuals with Cystic fibrosis?

Answer 46

normal at birth, failure to thrive, recurrent pneumonia, sputum with pseudomonas scattered tales/crackles throughout lungs axillary sweat test Bronchiectasis; respiratory defect is the most common cause of death

Question 47

Where is the defect seen in Familial Hypercholesterolemia (FH)?

Answer 47

protein folding defect defective transport from RER to Golgi

Question 48

What is mutated in FH?

Answer 48

mutation of LDL-R which is the cell surface receptor for LDL; it's a transmembrane protein

Question 49

Which class of FH did we study in class?

Answer 49

Class II

Question 50

What is the mode of inheritance for FH?

Answer 50

Genetically related inheritance (Familial)

Question 51

What is the mechanism seen with the defect in FH?

Answer 51

mutation inhibits protein folding of LDL-R | ejected from ER, polyubiquinated (KNOW THIS), degraded by proteasome

Question 52

What are some common characteristics seen in individuals with FH?

Answer 52

increased plasma cholesterol levels; increased LDL synthesis; major risk for CHD, premature atherosclerosis, Xanthomata, corneal arcus, Xanthelasmata

Question 53

What kind of disease is I-Cell disease also considered to be?

Answer 53

LYSOSOMAL STORAGE DISEASE

Question 54

Where is the defect seen in I-cell disease?

Answer 54

transport defect - absence of M6P-tag due to a N-acetylglucosamine (GlcNAc) phosphotransferase deficiency in the cis-golgi

Question 55

What is the mode of inheritance for I-cell disease?

Answer 55

Autosomal recessive

Question 56

What is the mechanism associated with the defect in I-cell disease?

Answer 56

absence of M6P tag results in lysosomal enzymes being sent to PM and secreted extracellularly, rather than being sent to lysosomes NO breakdown of cellular inclusions in lysosomes asa result accumulation of inclusions

Question 57

A point of confusion: In I-Cell disease, where is the defect NOT seen that people often confuse as the cause?

Answer 57

NO defect in the lysosomal enzymes rather, defect in Golgi-resident modification enzyme responsible for tagging with M6P

Question 58

What are some characteristics associated with I-Cell disease?

Answer 58

progressive disease; high levels of acid hydrolases in the blood; skeletal abnormalities; coarse facial features (HINT), psychomotor retardation (HINT), splenomegaly death due to CHF or RTI

Question 59

What is the life expectancy for an individual afflicted with I-Cell disease?

Answer 59

~10 years

Question 60

How many diseases are associated with defects in Exocytosis & Endocytosis that we've discussed?

Answer 60

3

Question 61

What are the 3 diseases associated with Exo and Endocytosis?

Answer 61

Botulism Tetanus Familial Hypercholesterolemia (Seen previously with RER/Golgi)

Question 62

Where is the defect seen with Botulism?

Answer 62

inhibition of SNARE/exocytosis

Question 63

What is the mode of inheritance of Botulism? How is it acquired?

Answer 63

from Clostridium botulinum toxin; often foodborne, wound, infants eating off the floor

Question 64

What is the mechanism associated with the defects caused by Botulism?

Answer 64

cleaves synaptobrevin (v-SNARE) (HINT) of vesicles carrying ACh; unable to interact with syntaxin (t-SNARE); inhibits exocytosis/release of ACh at neuromuscular junction

Question 65

What are the characteristics associated with Botulism patients?

Answer 65

paralysis of respiratory and skeletal muscles (potentially fatal) because stimulatory neurotransmitter ACh is not released to elicit musle contraction; Flaccid paralysis

Question 66

What syndrome is associated with Botulism? What are the symptoms?

Answer 66

Floppy Baby Syndrome hypotonia, hyporeflexia