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M2M exam 2 > mutational mechanism and disease > Flashcards

mutational mechanism and disease Flashcards

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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
functions of mutation in beta hemoglobin gene:
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
26
Consequences of hemoglobin kempsey
Hb Kempsey unloads less oxygen in tissues Body ‘thinks’ it needs more oxygen --> makes more red blood cells --> polycythemia
27
Charcot Marie Tooth Syndrome Type IA gene mutation
Duplication of PMP22 gene = Gain-of-function | --> Charcot Marie Tooth Syndrome type IA (CMT1A)
28
PMP22 protein is an
integral membrane glycoprotein in nerves
29
CMT 1A | clinically
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
30
examples of novel property mutations
sickle cell anemia
31
sickle cell anemia mutation
No effect on oxygen carrying ability of hemoglobin Novel property of polymerizing under low oxygen conditions Long hemoglobin polymers --> sickle cell shape
32
In Osteogenesis type I
loss of function mutations --> ½ the amount of total collagen trimers, but it is all normal --> mild phenotype
33
In Osteogenesis types II, III, IV
novel property mutations - -> relatively ‘normal’ amount of total collagen trimers, but ½ is abnormal - -> severe phenotype
34
Lesson: better to have_____ normal collagen, than ________ trimers
½ the amount of produce abnormal collagen
35
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
yep
36
consequences of mutations
``` Some key factors: Type of mutation Severity of mutation Target of mutation Protein (target) acts alone versus part of larger network ```
37
protein classes where mutations occur
``` Enzymes receptors Transporters structural nuclear extra-cellular secreted mitochondrial ```
38
Tri/tetra nucleotide repeat disorders
1. unstable repeat disorders 2. largely neurodegenerative 3. genetic anticipation
39
Trinucleotide repeat disorders can affect ______
different parts of a gene (5’, 3’, introns, exons)
40
fragile X sydrome trinucleotide repeats are located
CGG 5'UTR txn silencing loss of function loss of RNA binding--> impaired translational repression of target RNAs
41
Fragile X tremor/ataxia syndrom trinucleotide located
``` 5' UTR CGG repeats 2-5 fold increase in FMR1 mRNA gain of mRNA function neuronal intranuclear inclusions ```
42
Fredreich ataxia trinucleotide repeats
``` GAA intron impaired txn elongation loss of function increased Fe in mit reduced heme synthesis redusced Fe-S complex containing protein ```
43
Myotonic dystrophy 2 | trinucleotide repeats
CCTG intron expanded CUG repeat in RNA increased binding of RNA binding proteins
44
huntington''s disease trinucleotide repeats
CAG exon expands polyglutamine tracts in huntington protein loss of function of protein
45
Myotonic dystrophy 1 trinucleotide repeats
CUG 3' UTR expanded CUG repeats in RNA confer to increase amount os RNA binding proteins
46
correlation btwn CAG and onset huntingtons
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
Fragile X (_______), Friedreich ataxia (______), and some spinocerebellar ataxias (_______
x linked autosomal recessive mostly autosomal dominant, but recessive forms are also reported
48
Genetic anticipation describes
describes the clinical observation of disease severity worsening in subsequent generations.
49
Genetic anticipation is explained by
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
3 principal pathogenic mechanism
class 1 2 3
51
class 1 mechanism
Expansion of noncoding repeats and loss of | function
52
class 1 consequences
Impaired transcription - Mutant RNA not made - - Mutant protein not made
53
class 1 exampels
fragile x | friedreich ataxia
54
class 2 mechanism
expansion of noncoding repeats conferring novel properties
55
class 2 consequnces
``` 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
class 2 examples
mytotonic dystrophy 1 and 2 fragile X associated tremor/ataxia (FXTAS)
57
class 3 mechanism
expansions of codons in exons
58
class 3 consequences
1. novel properties on expressed protein 2. mutant RNA is made 3. protein is made and IS TOXIC
59
class 3 examples
1. huntingtons | 2. spinocerebellar ataxia
60
Loss-of-Function Mutations: | Mechanisms:
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
Complete loss of a protein: stop codon, frameshift, or deletion of multiple exons is seen in
Duchenne Muscular dystrophy
62
Reduction in amount of protein: deletion of copy of
alpha-thalassemia gene
63
Loss of entire chromosome:
Loss of entire chromosome: Turner syndrome
64
Somatic mutation leading to loss of tumor suppressor protein:
2nd hit in hereditary | retinoblastoma
65
Hereditary neuropathy with liability to pressure palsies (HNPP): due to
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
Osteogenesis imperfecta type I: is an example of
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
Gain-of-Function Mutations: | Mechanisms:
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
hemoglobin kempsey gene is
beta hemoglobin gene with asp99Asn mutation
69
achondroplasia gene and mutation
FGFR3 Gly380ARg
70
Alzheimers disease gene
APP protein | 21q21
71
charcot marie tooth gene
PMP22
72
sickle cell anemia gene
Glu6Val
73
huntington's disease gene
CAG codon repeat expansion
74
Ectopic or Heterochronic Expression Mutations: Mechanisms:
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
examples of novel property mutations include
cancer | hereditary persistence of fetal hemoglobin
76
unstable repeat sequences
increases from parent to offspring | huntington's disease

M2M exam 2 (23 decks)

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