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M2M2 > Mutational Mechanism of Disease > Flashcards

Mutational Mechanism of Disease Flashcards

1
Q

What are the causes (mutational) of disease

A

loss of function (most common)
gain of function
novel property
ectopic or heterchromic expression

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2
Q

Loss of function mutations

A

Single gene disorders almost always result from mutations that alter function of a protein

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3
Q

The majority of mutations will affect __________-

A

the function of a protein

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4
Q

Examples of loss of function

A

Duchenne muscular dystrophy

Hereditary neuropathy with liability to pressure palsies

Osteogenesis imperfecta

Alpha thalassemia

Turner

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5
Q

DMD

Chromosome

A

Xp21.2

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6
Q

DMD

Mutation?

A

Large deletion (multiple exons)
or
Nonsense (stop) mutation / frameshift –> premature termination

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7
Q

DMD

inheritance pattern?

A

X linked

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8
Q

DMD

Clinical

A

Boys with abnormal gain 3-5y/o
Calf pseudohypertrophy
Progressive involvement of respiratory muscles

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9
Q

DMD women?

A

Women may–>cardiomyopathy

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10
Q

DMD median death

A

18

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11
Q

Xp21.2

A

DMD

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12
Q

Hereditary neuropathy with liability to pressure palsies

Mutation?

A

Deletion of PMP22

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13
Q

PMP22 deleted in

A

HNPP mutation

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14
Q

PMP22 (HNPP) what is it’s function

A

integral membrane glycoprotein in nerves

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15
Q

HNPP (PMP22 deletion)

clinical

A

Repeated focal pressure neuropathies (carpal tunnel, peroneal palsy w/ foot drop)

First attack usually in 2nd-3rd decade

Recovery from acute neuropathy is often complete

Incomplete recovery –> mild disability

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16
Q 
PMP22 deletion (HNPP)
inheritance?
A

Autosomal dominant

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17
Q 
PMP22 deletion (HNPP)
most common cause
A

Unequal crossover between homologous repeats on 17p12

–> 3 copies PMP22 on one chromosome and 1 copy PMP22 on the other

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18
Q

PMP22 deletion –>

A

HNPP

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19
Q

PMP22 duplication –>

A

CMT1A

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20
Q

17P12 associated with

A

deletion - HNPP

duplication - CMT1A

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21
Q

What kind of disorders are HNPP and CMT1A

A

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

22
Q

Allelic disorder

A

conditions that are genetically related due to the same gene (most commonly)

23
Q

Osteogenesis imperfecta Type I

What type of mutation?

A

Loss of function

24
Q

Osteogenesis imperfecta type I

Clinical?

A

Brittle bones
increased fractures (non-deforming)
blue sclerae
normal stature

progressive hearing loss

25
Q

OI type I

Gene effected

A

Premature termination codons (or frameshift) in COL1A1

26
Q

OI type I

Inheritance pattern

A

Autosomal dominant

27
Q

OI type I
due to COL1A1 mutation
what happens?

A

Normally COL1A1 makes 2x pro-alpha1 fibers as COL1A2 makes pro-alpha2 fibers

Tertiary helix forms collagen

if we miss out on 1/2 pro-alpha1 due to mutated COL1A1 then our ratio is imbalanced and we get OI type I

28
Q

Hemoglobin Kempsey
What type of mutation?
What is the mutation?

A

Gain of function

Beta globin gene Asp99Asn missense mutation

29
Q

What is the consequence of Hemoglobin Kempsey mutation?

A

Higher oxygen affinity
“locked” in relaxed state
body think need more oxygen –> polycythemia

30
Q

Charcot Marie Tooth Syndrome Type IA
Type of mutation?
Genetic Cause

A

Gain of function

Duplication of PMP22 gene

31
Q

CMT1A

Clinical

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

32
Q

CMT1A inheritance pattern

A

Autosomal dominant

33
Q

Sickle Cell anemia

Type of mutation?

A

Novel function

34
Q

If sickle cell anemia is a novel function mutation, what is the novel property?

A

Polymerization under low oxygen conditions

35
Q

Does SS effect oxygen carrying ability of hemoglobin?

A

no

36
Q

What happens in osteogenesis imperfecta Types II, III, and IV

A

Novel property mutations –> relatively normal amount of total collagen trimers, but 1/2 is abnormal shape –> severe phenotype

37
Q

Would you rather have OI type I or OI type II (III or IV)

A

I would rather have OI type I because that is a loss of function - but I still make 1/2 the amount of normal

Type II, III, IV I make 1/2 fucked up (novel property) and this fucks up everything - so no

38
Q

What type of mutation is hereditary persistance of fetal hemoglobin due to?

A

Altered expression pattern mutation - express fetal hemoglobin rather than adult - sometimes because adult gamma and beta have been deleted

39
Q

Tri/Tetra nucleotide repeat disorders
Largely effect?
Common characteristic?

A

Largely neurodegenerative

Anticipation

40
Q

What happens in Huntington disease - we know that there is a trinucleotide repeat - but what is the consequence?

A

Novel properties to Huntingtin protein

INcreased and or promiscuous protein protein interaction with transcription factors –> loss of their function

41
Q

Where do trinucleotide repeats effect a gene?

A 
can be anywhere
5'
3'
intron
exon
42
Q

Where does fragile X target?

Remember it is CGG expansion

A

5’ UTR

causing transcriptional silencing

43
Q

Where does Myotonic dystrophy 1 target?

Remember it is CUG expansion.

A

3’UTR –> impaired RNA splicing of key proteins (because binds RNA binding proteins)

44
Q

Where does Huntingtons disease target

Remember CAG repeat

A

Exon

Yields novel protein properties / promiscuous interactions

45
Q

Huntington disease
There is a correlation between age of onset and number of CAG repeats, how many CAG repeats are typically required to see disease?

A

40

46
Q

Is Huntington mom’s or dad’s fault?

A

Dads

47
Q

Myotonic Dystrophy
inheritance
cause

A

autosomal dominant

repeat CTG expansion in DMPK (mom’s fault)

48
Q 
Myotonic dystrophy 
CTG repeat size 
Normal
Mild 
Classic 
Congenitle
A

35 -49
50-150
100-1000
>2000

49
Q

Clinical and age of onset/death MD

Mild (50-150)

A

Cataracts
Mild myotonia
20/70 – 60+

50
Q

Clinical and age of onset/death MD

Classic (100-1000)

A 
Weakness
Myotonia 
Cataracts
Balding 
Cardiac arrhythmias

10-30 –> 48-55

51
Q

Clinical and age of onset/death MD

Congenital (2000+)

A

Infantile hypotonia
Respiratory deficits
ID
Birth - 10 — 45yr

M2M2 (27 decks)

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