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Medical Biochemistry > Molecular mechanisms in inherited disorders > Flashcards

Molecular mechanisms in inherited disorders Flashcards

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USMLE® Step 1 flashcards
1
Q

Mutation in what proteins results in Cystic Fibrosis?

A

Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)

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2
Q

What is CFTR?

A

membrane protein that acts as a chloride channel

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3
Q

CFTR belongs to what group of transporters?

A

group of ATP Binding Cassette (ABC) transporter

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4
Q

Describe the structure (domains) of CFTR?

A

It has 2 membrane spanning domains, two ATP binding domains and a regulatory domain that can be phosphorylated.

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5
Q

What causes activation of CFTR?

A

phosphorylation of regulatory domain by PKA

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6
Q

Why is there low Na and H20 in the lumen (mucous)?

A

the mutant CPTR can’t transport Cl from the cell into the lumen therefore Na will stay in cell to balance Cl’s negative charge.

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7
Q

Why is the mucous thick and viscid in pts w/ Cystic Fibrosis?

A

due to the low water and electrolyte concentration in the mucous.

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8
Q

Why do CF pts have a higher risk of developing respiratory infections?

A

The thick viscid mucus are prone to developing bacterial infections.

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9
Q

Respiratory infections are common causes of what in CF pts?

A

mortality and morbidity

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10
Q

How does the mutant CFTR effect the pancreas?

A

Leads to thick pancreatic secretions which obstruct pancreatic duct and destroy tissue. Results in deficiency of pancreatic enzymes.

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11
Q

What type of tissues replace pancreatic tissue in pts with cystic fibrosis?

A

Fibrotic tissue and fat

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12
Q

What symptoms are found in pts with CF?

A

Malabsorption, sterility, salty sweat, chronic pancreatitis, secondary biliary cirrhosis and recurring resp infections

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13
Q

Why is there defective protein digestion in pts with CF?

A

Blockage of pancreatic duct results in deficient secretion of pancreatic enzymes like lipase, trypsin, and chymotrypsin

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14
Q

Why is there steatorrhea in pts w/ CF?

A

B/C of the maldigestion of nutrients and the excretion of fat in stool due to deficiency of fat soluble vitamins esp Vit K (not stored in liver)

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15
Q

Why do many children w/ CF have protein malnutrition and delay in growth?

A

B/C of the deficient secretion of pancreatic enzymes which aid in the digestion of proteins

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16
Q

How is it possible to restore normal digestion and nutrition in pts w/ CF?

A

by providing pancreatic enzyme supplements

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17
Q

The viscid secretions in the intestine of CF pts causes what in kids?

A

meconium ileus and intestinal obstruction

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18
Q

Why are more than 95% of males with CF infertile?

A

B/C they don’t have a vas deferens; called Congenital bilateral absence of the vas deferens (CBAVD)

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19
Q

What is the normal role of CFTR in sweat glands?

A

to reabsorb NaCl from the sweat.

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20
Q

How is the role of CFTR different in sweat glands compared to that in lungs/ pancreas?

A

CFTR reabsorbs NaCl in sweat glands while in other tissues, it secretes Cl (opposite fxns)

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21
Q

The presence of excessive salt in sweat is diagnostic of what condition?

A

Cystic fibrosis

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22
Q

What chromosome contains the mutation for CFTR?

A

chromosome 7

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23
Q

What is the most common position for the mutation that results in CFTR?

A

position 508 (F508)

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24
Q

Is Cystic Fibrosis a x-linked disorder?

A

No, autosomal recessive disorder

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25
Q

What is the most common CFTR mutation and on what domain is it on?

A

3 bp deletion that eliminates phenylalanine residue from the ATP binding domain 1

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26
Q

What is the effect of phenylalanine deletion at position 508 on CFTR structure?

A

doesn’t cause change in reading frame but prevents protein from maturing and from reaching the plasma membrane

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27
Q

What drug is used to stimulate sweat glands in the sweat chloride test?

A

pilocarpine - used to collect sweat to measure chloride concentration in diagnosis of CF

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28
Q

What molecular diagnostic tests an be used to determine CF if the mutation is known?

A

ASO and Allele specific PCR test

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29
Q

Why is it possible to use PCR and Southern blotting to detect F508 mutations in pts w/ CF?

A

B/C the mutant gene (60 bp) is shorter than the normal gene (63pb) by 3 bp

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30
Q

Describe the G protein pathway involved in CFTR.

A

activated G-protein coupled receptor will activate adenylate cyclase which will increase levels of cAMP. this activates protein kinase A (PKA) to phosphorylate CFTR. This opens channel so that Cl can leave.

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31
Q

What type of mutation causes sickle cell anemia?

A

point mutation in 6th position of B-globin chain of hemoglobin where glutamic acid is replaced by valine

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32
Q

At what position does the point mutation occur?

A

postion 6 of B-globin chain of Hb

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33
Q

What effect does the substitution of valine for glutamic acid have on the structure of Hb?

A

Will create a hydrophobic pocket on the exterior surface of Hb b/c valine is hydrophobic and glutamic acid is hydrophobic

34
Q

Why does Hb tend to aggregate, forming long filament like structures in pts w/ sickle cell anemia?

A

the mutation will create a hydrophobic pocket “sticky patch” forming site of attachment for nearby Hb molecules.

35
Q

What effect does aggregation of Hb molecules have on the structure of RBC?

A

Distorts structure of RBC- sickled shape

36
Q

What is the effect of sickled RBC on Bl flow?

A

blocks bl flow b/c can’t flow freely

37
Q

Why do pts w/ sickle cell disease have anemia?

A

b/c the spleen removes the sickled and distorted RBCs often

38
Q

Why would splenomegaly be present in pts w/ sickle cell disease?

A

B/c spleen is responsible for removing the sickled RBCs

39
Q

What type of hyperbilirubinemia in found in sickle cell disease?

A

Pre-hepatic (hemolytic type)

40
Q

What type of bilirubin accumulates in pts w/ Sickle cell anemia?

A

unconjugated (direct) and total bilirubin

41
Q

Why will jaundice be present in pts w/ sickle cell anemia?

A

b/c of the excessive removal of sickled RBC from the bloood

42
Q

Why is the urine of pts w/ sickle cell anemia normal?

A

the high levels of unconjugated bilirubin can’t be excreted in urine b/c bound to albumin

43
Q

Why will people w/ sickle cell anemia develop pigmented gall stones?

A

b/c large amounts of conjugated bilirubin are secreted into bile

44
Q

In electrophoresis, why would HbS (sickle cell form) move slower than HbA toward the positive end?

A

HbS has valine which is less negative than the glutamate in HbA (normal)

45
Q

Why is it useful to use ASO test to detect sickle cell disease?

A

Makes it possible to identify carriers

46
Q

What does RFLP analysis reveal about sickle cell disease and carriers in relation to restriction sites?

A

Normal: 3 restriction sites; in sickle cell anemia: loss of central restriction site producing longer fragment generated which will travel more slowly than normal band

47
Q

What gene is mutant in Duchenne muscular dystrophy and Becker muscular dystrophy?

A

Dystrophin gene

48
Q

Almost complete absence of functional dystrophin results in what disease?

A

Duchenne Muscular Dystrophy (DMD)

49
Q

What causes Becker Muscular Dystrophy?

A

production of abnormal dystrophin or decreased amts of dystrophin

50
Q

Why is Duchenne Muscular Dystrophy more common in males?

A

X-linked recessive disease

51
Q

What is the most common muscular dystrophy?

A

DMD

52
Q

Which muscular dystrophy is more milder? which muscular dystrophy has a later onset?

A

Becker Muscular Dystrophy for both b/c DMD will occur between ages 2-6 and most pts die in early 20s.

53
Q

What is the differences between DMD deletions and BMD deletions?

A

DMD: cause frameshift mutations resulting in large deletions of exons (almost no protein)

BMD: in-frame mutations therefore protein is shorter but translated

54
Q

Why will pts w/ DMD and BMD have trouble rising, climbing stairs and maintaining balance?

A

b/c DMD and BMD affects pectoral muslces, trunk and upper/lower legs -muscle weakness

55
Q

What is Gowers’ maneuver?

A

distinctive way of risking from floor: get on hands/knees first, raise posterior, then “walk” hands up legs to raise their upper body

56
Q

Gowers’ manuever is characteristic of what disease and why?

A

Duchenne muscular dystrophy; b/c of weakened leg muscles

57
Q

What would lead to pseudohypertrophy and in what disease is it found?

A

replacement of normal muscle w/ connective tissue / fat; in pts with DMD

58
Q

The largest gene encodes for what protein and where is it found?

A

Encodes for dystrophin; expressed in smooth, cardiac and skeletal muscle w/ lower levels in the brain

59
Q

Why would cardiac abnormalities be found in pts w/ DMD resulting in their early death?

A

b/c gene for dystrophin also expressed in cardiac muscle

60
Q

Describe structure of Dystrophin

A

has two globular heads with flexible rod-shaped center. One head binds to actin; other head (C-terminal domain) binds to protein in plasma membrane

61
Q

How does Dystrophin anchor cystoskeleton of muscle cells to extracellular matrix?

A

by linking actin filaments to transmembrane proteins of muscle cell plasma mem.

62
Q

Why is Dystrophin important?

A

Its role in anchorage of cytoskeleton to EC matrix stabilizes plasma mem and helps cell to withstand stress of muscle contraction.

63
Q

What does the loss of dystrophin result in?

A

oxidative cellular injury and myonecrosis

64
Q

How can we differentiate between DMD and BMD in western blot?

A

DMD: no band b/c of frameshift deletion; BMD: smaller protein size and decreased quantity when compared to normal

65
Q

Microscopy of BMD/ DMD will show what when compared to normal?

A

increase in adipocytes and fibrous tissue

66
Q

What will immunofluorescense microscopy show in pts w/ DMD, BMD?

A

BMD: reduced quantity of dystrophin; DMD: complete absence

67
Q

What are serum creatine kinase (MM) in pts w/ muscular dystrophy?

A

high b/c CK MM indicates muscle damage

68
Q

What is the serum CK-MM levels in females who are carriers for DMD?

A

high levels

69
Q

Gowers’ manuever is characteristic of what disease and why?

A

Duchenne muscular dystrophy; b/c of weakened leg muscles

70
Q

What would lead to pseudohypertrophy and in what disease is it found?

A

replacement of normal muscle w/ connective tissue / fat; in pts with DMD

71
Q

The largest gene encodes for what protein and where is it found?

A

Encodes for dystrophin; expressed in smooth, cardiac and skeletal muscle w/ lower levels in the brain

72
Q

Why would cardiac abnormalities be found in pts w/ DMD resulting in their early death?

A

b/c gene for dystrophin also expressed in cardiac muscle

73
Q

Describe structure of Dystrophin

A

has two globular heads with flexible rod-shaped center. One head binds to actin; other head (C-terminal domain) binds to protein in plasma membrane

74
Q

How does Dystrophin anchor cystoskeleton of muscle cells to extracellular matrix?

A

by linking actin filaments to transmembrane proteins of muscle cell plasma mem.

75
Q

Why is Dystrophin important?

A

Its role in anchorage of cytoskeleton to EC matrix stabilizes plasma mem and helps cell to withstand stress of muscle contraction.

76
Q

What does the loss of dystrophin result in?

A

oxidative cellular injury and myonecrosis

77
Q

How can we differentiate between DMD and BMD in western blot?

A

DMD: no band b/c of frameshift deletion; BMD: smaller protein size and decreased quantity when compared to normal

78
Q

Microscopy of BMD/ DMD will show what when compared to normal?

A

increase in adipocytes and fibrous tissue

79
Q

What will immunofluorescense microscopy show in pts w/ DMD, BMD?

A

BMD: reduced quantity of dystrophin; DMD: complete absence

80
Q

What are serum creatine kinase (MM) in pts w/ muscular dystrophy?

A

high b/c CK MM indicates muscle damage

81
Q

What is the serum CK-MM levels in females who are carriers for DMD?

A

higher levels

Medical Biochemistry (35 decks)

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