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M2M exam 2 > mutational mechanism and disease > Flashcards

mutational mechanism and disease Flashcards

1
Q

single gene disorders

A
  1. loss of function
  2. gain of function
  3. novel property mutation
  4. altered expression mutations
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2
Q

The majority of mutations (currently known) will affect the ______ of the protein

A

function

Loss of function mutations are the most common example of this

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3
Q

Of the four major mechanisms, this is the most common genetic mechanism leading to human genetic disease.

A

loss of function

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4
Q

loss of function caused by

A

by genetic mutations (deletions, insertions, or rearrangements) that eliminate (or reduce) the function of the protein

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5
Q

loss of function examples

A
  1. duchenne muscular dystrophy
  2. a-thalassemia
  3. turner syndrome
  4. hereditary neuropathy with liability to pressure palsies
  5. osteogenesis
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6
Q

Duchenne muscular dystrophy (Case 12):

A 
DMD Xp21.2
Large deletions (multiple exons)
Nonsense (stop) mutations / frameshift mutations 
--> premature termination
(in-frame deletions 
--> milder Becker muscular dystrophy)
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7
Q

Alpha-thalassemia (Case 39)

A

Alpha-thalassemia (Case 39)

Deletion of alpha globin gene(s)

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8
Q

Turner syndrome (Case 42)

A

Chromosome deletion

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9
Q

Hereditary neuropathy with liability to pressure palsies

A

Deletion of gene
(duplication
–> Charcot Marie tooth)

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10
Q

Osteogenesis imperfecta type I

A

Nonsense (stop) mutations / frameshift mutations

–> premature termination

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11
Q

DMD Xp21.2

A 
Large deletions (multiple exons)
Nonsense (stop) mutations / frameshift mutations 
--> premature termination
(in-frame deletions 
--> milder Becker muscular dystrophy)
X-linked inheritance
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12
Q

DMD stands for

A

duchenne muscular dystophy

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13
Q

DMD clinically:

A 
Boys with abnormal gait at 3-5 years
Calf pseudohypertrophy
Gower maneuver (YouTube)
Progressive involvement of respiratory muscles
Median age of death 18 years
Women may 
--> cardiomyopathy
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14
Q

DMD deletions

A

Frameshift deletions = major loss-of-function mechanism in Duchenne Muscular Dystrophy
In-frame deletions (and also missense mutations) = major loss-of (i.e. reduction)-function in Becker Muscular dystrophy

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15
Q

Hereditary neuropathy with liability to pressure palsies

mutations

A

Deletion of PMP22 gene = Loss-of-function
–>Hereditary Neuropathy with Liability to Pressure Palsies (HNPP)
PMP22 protein is an integral membrane glycoprotein in nerves

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16
Q

Hereditary neuropathy with liability to pressure palsies

clinically

A

repeated focal pressure neuropathies (e.g. carpal tunnel syndrome and peroneal palsy with foot drop)
First attack usually in 2nd-3rd decade

Recovery from acute neuropathy is often complete
Incomplete recovery
–> mild disability

Autosomal Dominant

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17
Q

Unequal crossing over between two highly homologous repeats on chromosome 17p12 can result in:

A

A. 3 copies of the PMP22 gene with the CMT1A phenotype or

B. the reciprocal with 1 copy of the PMP22 gene with the HNPP phenotype.

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18
Q

HNPP and CMT1A are

A

allelic disorders in the sense that different mutations in the same gene lead to different phenotypes

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19
Q

‘Allelic disorders’ refer to conditions that are

A

genetically related (due to the same gene most commonly)

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20
Q

Osteogeneis Imperfecta Type I

clinically:

A

Brittle bones, increased fractures (non-deforming)
blue sclerae
normal stature.
First fracture may occur with diapering, but more typically once infant begins to walk (and fall)
Affected individuals may have anywhere from a few fractures to more than 100M
Progressive hearing loss in adults

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21
Q

OI 1 pathway

A

Premature termination codons (nonsense and frameshift) in COL1A1

  • -> mRNA unstable
  • -> mRNA degraded
  • -> reduction of normal COL1A1 protein

Autosomal Dominant

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22
Q

OI 1 affects:

A

The structure of type I procollagen. Note that type I procollagen is composed of two proα1(I) chains and one proα2(I) chain

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23
Q

examples of gain of function

A

hemoglobin Kempsey

Charcot Marie Tooth Syndrome Type IA

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24
Q

hemoglobin Kempsey gene and mutation

A

Beta hemoglobin gene

Asp99Asn missense mutation

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25
Q

functions of mutation in beta hemoglobin gene:

A
  1. Higher oxygen affinity
  2. In normal hemoglobin binding of oxygen allowing for shift from tense (deoxygenated) to relaxed (oxygenated) form
    99Asn mutation prevents this shift
  3. Hemoglobin remains ‘locked’ in the relaxed state (which has higher
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26
Q

Consequences of hemoglobin kempsey

A

Hb Kempsey unloads less oxygen in tissues
Body ‘thinks’ it needs more oxygen
–> makes more red blood cells
–> polycythemia

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27
Q

Charcot Marie Tooth Syndrome Type IA

gene mutation

A

Duplication of PMP22 gene = Gain-of-function

–> Charcot Marie Tooth Syndrome type IA (CMT1A)

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28
Q

PMP22 protein is an

A

integral membrane glycoprotein in nerves

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29
Q

CMT 1A

clinically

A

Demyelinating motor and sensory neuropathy
Often presents in lower extremities with weakness and muscle atrophy and mild sensory loss
Progressive; typical patterns on nerve conduction studies
Autosomal Dominant

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30
Q

examples of novel property mutations

A

sickle cell anemia

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31
Q

sickle cell anemia mutation

A

No effect on oxygen carrying ability of hemoglobin

Novel property of polymerizing under low oxygen conditions

Long hemoglobin polymers
–> sickle cell shape

32
Q

In Osteogenesis type I

A

loss of function mutations –> ½ the amount of total collagen trimers, but it is all normal –>
mild phenotype

33
Q

In Osteogenesis types II, III, IV

A

novel property mutations

  • -> relatively ‘normal’ amount of total collagen trimers, but ½ is abnormal
  • -> severe phenotype
34
Q

Lesson: better to have_____ normal collagen, than ________ trimers

A

½ the amount of

produce abnormal collagen

35
Q

An understanding of the mutation –>

May provide insight into the molecular mechanism (loss of function, gain of function, etc)
–>

May provide clues to the inheritance pattern –>

May set the stage for developing therapies

A

yep

36
Q

consequences of mutations

A 
Some key factors:
Type of mutation
Severity of mutation
Target of mutation
Protein (target) acts alone versus part of larger network
37
Q

protein classes where mutations occur

A 
Enzymes
receptors
Transporters
structural
nuclear
extra-cellular
secreted
mitochondrial
38
Q

Tri/tetra nucleotide repeat disorders

A
  1. unstable repeat disorders
  2. largely neurodegenerative
  3. genetic anticipation
39
Q

Trinucleotide repeat disorders can affect ______

A

different parts of a gene (5’, 3’, introns, exons)

40
Q

fragile X sydrome trinucleotide repeats are located

A

CGG 5’UTR
txn silencing
loss of function
loss of RNA binding–> impaired translational repression of target RNAs

41
Q

Fragile X tremor/ataxia syndrom trinucleotide located

A 
5' UTR
CGG repeats
2-5 fold increase in FMR1 mRNA
gain of mRNA function
neuronal intranuclear inclusions
42
Q

Fredreich ataxia trinucleotide repeats

A 
GAA
intron
impaired txn elongation
loss of function
increased Fe in mit
reduced heme synthesis
redusced Fe-S complex containing protein
43
Q

Myotonic dystrophy 2

trinucleotide repeats

A

CCTG
intron
expanded CUG repeat in RNA
increased binding of RNA binding proteins

44
Q

huntington’’s disease trinucleotide repeats

A

CAG
exon
expands polyglutamine tracts in huntington protein
loss of function of protein

45
Q

Myotonic dystrophy 1 trinucleotide repeats

A

CUG
3’ UTR
expanded CUG repeats in RNA confer to increase amount os RNA binding proteins

46
Q

correlation btwn CAG and onset huntingtons

A

Allele sizes (# of CAG repeats)
Normal: < 26
Intermediate: 27-35 (no symptoms; risk of expansion)
Disease +/-: 36-39 (reduced penetrance; risk of expansion)
Disease +: > 40 (~100 % disease; risk of expansion)

47
Q

Fragile X (_______), Friedreich ataxia (______), and some spinocerebellar ataxias (_______

A

x linked

autosomal recessive

mostly autosomal dominant, but recessive forms are also reported

48
Q

Genetic anticipation describes

A

describes the clinical observation of disease severity worsening in subsequent generations.

49
Q

Genetic anticipation is explained by

A

the mechanism of tri/tetra nucleotide repeat number expansions occurring from parent to offspring. The offspring inheriting an expanded disease allele is more likely to present earlier and progress faster.

50
Q

3 principal pathogenic mechanism

A

class 1
2
3

51
Q

class 1 mechanism

A

Expansion of noncoding repeats and loss of

function

52
Q

class 1 consequences

A

Impaired transcription

  • Mutant RNA not made -
  • Mutant protein not made
53
Q

class 1 exampels

A

fragile x

friedreich ataxia

54
Q

class 2 mechanism

A

expansion of noncoding repeats conferring novel properties

55
Q

class 2 consequnces

A 
1. RNA has novel property 
(abnormal RNA binds and soaks up RNA binding protein
--> affects other gene product)
2. mutant RNA is made
3. mmutant protein is not made
56
Q

class 2 examples

A

mytotonic dystrophy 1 and 2
fragile X associated tremor/ataxia
(FXTAS)

57
Q

class 3 mechanism

A

expansions of codons in exons

58
Q

class 3 consequences

A
  1. novel properties on expressed protein
  2. mutant RNA is made
  3. protein is made and IS TOXIC
59
Q

class 3 examples

A
  1. huntingtons

2. spinocerebellar ataxia

60
Q

Loss-of-Function Mutations:

Mechanisms:

A

Caused by genetic mutations (deletions, insertions, or rearrangements) that eliminate (or reduce) the function of the protein. Of the four major mechanisms, this is the most common genetic mechanism leading to human genetic disease.

61
Q

Complete loss of a protein: stop codon, frameshift, or deletion of multiple exons is seen in

A

Duchenne Muscular dystrophy

62
Q

Reduction in amount of protein: deletion of copy of

A

alpha-thalassemia gene

63
Q

Loss of entire chromosome:

A

Loss of entire chromosome: Turner syndrome

64
Q

Somatic mutation leading to loss of tumor suppressor protein:

A

2nd hit in hereditary

retinoblastoma

65
Q

Hereditary neuropathy with liability to pressure palsies (HNPP): due to

A

deletion of
PMP22 gene leading to a phenotype where patients have temporary (usually reversible) neuropathy when pressure is applied to various nerves. Just as your arm may go to sleep if left in a certain position, these patients are more sensitive to pressure on nerves and their limbs can ‘go to sleep’ for longer periods of time (hours, days, to months)

66
Q

Osteogenesis imperfecta type I: is an example of

A

Nonsense (stop) mutations / frameshift mutations in COL1A1 –>
premature termination.

Reduced amount of normal COL1A1 (collagen) protein causing a ‘milder’ form of osteogenesis imperfect. Clinically characterized by increased fractures, brittle bones, and blue sclera.

67
Q

Gain-of-Function Mutations:

Mechanisms:

A

Caused by genetic mutations (often missense or sometimes promoter mutations) that enhance one or more normal functions of a protein (e.g. increased protein expression, increased half- life, decreased degradation, increased activity)

68
Q

hemoglobin kempsey gene is

A

beta hemoglobin gene with asp99Asn mutation

69
Q

achondroplasia gene and mutation

A

FGFR3

Gly380ARg

70
Q

Alzheimers disease gene

A

APP protein

21q21

71
Q

charcot marie tooth gene

A

PMP22

72
Q

sickle cell anemia gene

A

Glu6Val

73
Q

huntington’s disease gene

A

CAG codon repeat expansion

74
Q

Ectopic or Heterochronic Expression Mutations: Mechanisms:

A

Caused by genetic mutations that alter regulatory regions of a gene and alter either the timing (wrong time = heterochronic) or location (wrong place = ectopic) of expression.

75
Q

examples of novel property mutations include

A

cancer

hereditary persistence of fetal hemoglobin

76
Q

unstable repeat sequences

A

increases from parent to offspring

huntington’s disease

M2M exam 2 (23 decks)

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