Mutational Mechanism of Disease

Question 1

What are the causes (mutational) of disease

Answer 1

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

Question 2

Loss of function mutations

Answer 2

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

Question 3

The majority of mutations will affect __________-

Answer 3

the function of a protein

Question 4

Examples of loss of function

Answer 4

Duchenne muscular dystrophy

Hereditary neuropathy with liability to pressure palsies

Osteogenesis imperfecta

Alpha thalassemia

Turner

Question 5

DMD

Chromosome

Answer 5

Xp21.2

Question 6

DMD

Mutation?

Answer 6

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

Question 7

DMD

inheritance pattern?

Answer 7

X linked

Question 8

DMD

Clinical

Answer 8

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

Question 9

DMD women?

Answer 9

Women may–>cardiomyopathy

Question 10

DMD median death

Answer 10

18

Question 11

Xp21.2

Answer 11

DMD

Question 12

Hereditary neuropathy with liability to pressure palsies

Mutation?

Answer 12

Deletion of PMP22

Question 13

PMP22 deleted in

Answer 13

HNPP mutation

Question 14

PMP22 (HNPP) what is it’s function

Answer 14

integral membrane glycoprotein in nerves

Question 15

HNPP (PMP22 deletion)

clinical

Answer 15

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

Question 16

PMP22 deletion (HNPP)
inheritance?

Answer 16

Autosomal dominant

Question 17

PMP22 deletion (HNPP)
most common cause

Answer 17

Unequal crossover between homologous repeats on 17p12

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

Question 18

PMP22 deletion –>

Answer 18

HNPP

Question 19

PMP22 duplication –>

Answer 19

CMT1A

Question 20

17P12 associated with

Answer 20

deletion - HNPP

duplication - CMT1A

Question 21

What kind of disorders are HNPP and CMT1A

Answer 21

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

Question 22

Allelic disorder

Answer 22

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

Question 23

Osteogenesis imperfecta Type I

What type of mutation?

Answer 23

Loss of function

Question 24

Osteogenesis imperfecta type I

Clinical?

Answer 24

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

progressive hearing loss

Question 25

OI type I | Gene effected

Answer 25

Premature termination codons (or frameshift) in COL1A1

Question 26

OI type I | Inheritance pattern

Answer 26

Autosomal dominant

Question 27

OI type I due to COL1A1 mutation what happens?

Answer 27

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

Question 28

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

Answer 28

Gain of function | Beta globin gene Asp99Asn missense mutation

Question 29

What is the consequence of Hemoglobin Kempsey mutation?

Answer 29

Higher oxygen affinity "locked" in relaxed state body think need more oxygen --> polycythemia

Question 30

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

Answer 30

Gain of function | Duplication of PMP22 gene

Question 31

CMT1A | Clinical

Answer 31

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

Question 32

CMT1A inheritance pattern

Answer 32

Autosomal dominant

Question 33

Sickle Cell anemia | Type of mutation?

Answer 33

Novel function

Question 34

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

Answer 34

Polymerization under low oxygen conditions

Question 35

Does SS effect oxygen carrying ability of hemoglobin?

Answer 35

no

Question 36

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

Answer 36

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

Question 37

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

Answer 37

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

Question 38

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

Answer 38

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

Question 39

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

Answer 39

Largely neurodegenerative Anticipation

Question 40

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

Answer 40

Novel properties to Huntingtin protein | INcreased and or promiscuous protein protein interaction with transcription factors --> loss of their function

Question 41

Where do trinucleotide repeats effect a gene?

Answer 41

``` can be anywhere 5' 3' intron exon ```

Question 42

Where does fragile X target? | Remember it is CGG expansion

Answer 42

5' UTR | causing transcriptional silencing

Question 43

Where does Myotonic dystrophy 1 target? | Remember it is CUG expansion.

Answer 43

3'UTR --> impaired RNA splicing of key proteins (because binds RNA binding proteins)

Question 44

Where does Huntingtons disease target | Remember CAG repeat

Answer 44

Exon | Yields novel protein properties / promiscuous interactions

Question 45

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?

Answer 45

40

Question 46

Is Huntington mom's or dad's fault?

Answer 46

Dads

Question 47

Myotonic Dystrophy inheritance cause

Answer 47

autosomal dominant | repeat CTG expansion in DMPK (mom's fault)

Question 48

``` Myotonic dystrophy CTG repeat size Normal Mild Classic Congenitle ```

Answer 48

35 -49 50-150 100-1000 >2000

Question 49

Clinical and age of onset/death MD | Mild (50-150)

Answer 49

Cataracts Mild myotonia 20/70 -- 60+

Question 50

Clinical and age of onset/death MD | Classic (100-1000)

Answer 50

``` Weakness Myotonia Cataracts Balding Cardiac arrhythmias ``` 10-30 --> 48-55

Question 51

Clinical and age of onset/death MD | Congenital (2000+)

Answer 51

Infantile hypotonia Respiratory deficits ID Birth - 10 --- 45yr