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Flashcards in Mutational mechanism of disease Deck (29):
1

4 major mechanisms of genetic mutations that can lead to disease

1. loss of function
2. gain of function
3. novel property
4. altered expression mutations
- ectopic
- heterochronic

2

Duchenne muscular dystrophy
-affects what gene, resulting in what?

Dystrophin (DMD) X Xp21.2
resulting in complete loss of dystrophin protein

-loss of function

3

What type of inheritance pattern is Duchennes MD?

X linked recessive

4

Clinical signs of DMD?

abnormal gait 3-5 yrs old
calf hypertrophy
gower maneuver
progressive respiratory weakness
median age ~18
cariomyopathy

5

Hereditary neuropathy w/ liability to pressure palsis (HNPP)
-affects what gene, resulting in what? reciprocal of what?

deletion of PMP22 gene, resulting in no PMP protein
(pmp protein - imp membrane glycoprotein in nerves)

loss in function (recip of CMT)

6

What type of inheritance pattern is HNPP?

Autosomal dominant

7

Clinical signs of HNPP?

first attack in 2nd/3rd decade
repeated focal pressure neuropathies
carpal tunnel/peroneal palsy with foot drop
(similar to arm falling asleep if left in certain pos.

8

Osteogenesis Imperfecta Type I
-what gene is affected?
-resulting in what?

premature termination codons in COL1A1 resulting in loss of COL1A1 proein
(imp for bone development)

- triple helix protein structure is disrupted
(no more 2proalpha-1 and 1 proalpha2

- loss of function

9

What type of inheritance pattern is Osteogenesis Imperfecta Type I

autosomal dominant

10

Osteogenesis Imperfecta Type I
clinical signs

brittle bones
blue sclera
normal stature
progressive hearing loss in adults

11

hereditary retinoblastoma
affects what gene?

somatic mutation leading to loss of tumor suppressing gene (2-hit)

- loss of function

12

hemoglobin kempsey
-affects what gene, what type of mut on that gene, leading to what?

affects beta hemoglobin gene with a Asp99Asn missense mut.,

leading to Hb molecule with higher than normal oxygen affinity

-gain of function

13

alheimer's disease in trisomy 21
has what ch mut? leading to what?

3 copies of ch 21 and 3 copies of APP 21q21q, leading to increase in APP protein

-early onset alz

14

Charcot-marie-tooth (type 1A)
mut in what gene? leading to what? reciprocal of what?

duplication in PMP22 gene (3 copies),
leading to higher levels of PMP22 prot

-gain of funct (reciprocal of HNPP)

15

Sickle cell anemia
-mut in what gene? result in what?

Glu6Val mutation of beta globin gene

doesnt change Hb job - but novel property of polymerizing Hb into lng protein fibers under low oxygen conditions

-novel mut

16

Huntington's disease
repeat of what? resulting in what?

-CAG (glutamine)
-toxic effect on Ht protein

-novel mut

17

Osteogenesis Imperfecta type II, III, IV
Mut in what? resulting in what?

mut in COL1A1 gene - resulting in change of structure of COL1A1 protein

-more damaging when supply is there but material is useless (type I is better)

-novel mut

18

some cancers are what type of mutations? (1 of 4 major mech)

altered expression mutation (ectopic=wrong place)

gene that is normally silent is abnormally expressed and leads to abnormal proliferation

19

hereditary persistance of fetal hb
mut in what? resulting in what?

deletion of genes on beta Hb locus,
resulting in retention of fetal gamma gene.

20

Mechanism of hereditary persistance of fetal hb

heterochronic protein expression (wrong time)

normal switch from fetal to adult Hb does not occur, and fetal Hb (which has higher affinity for oxygen), remains expressed beyond infancy

21

8 steps at which mutation can disrupt product of normal protein

1. transcription
2.translation
3. polypeptide folding
4. postranslational modification

5. assembly of monomers into holomeric protein
6. subcellular localization of the polypeptide or holomer
7. cofactor/prosthetic group binding to polypeptide
8. function of a correctly folded, assembled,and localized protein produced in normal amounts

22

Name which step the mutation is disrupting:
- familial hypercholesterolemia

subcellular localization of polypeptide of holomer

23

Name which step the mutation is disrupting:
-hemoglobinopathies (hammersmith)

polypeptide folding

24

Name which step the mutation is disrupting:
Hb kempsey

function of correctly folded, assembled, and localized protein produced in normal amounts

25

Name which step the mutation is disrupting:
thalassemia
hereditary persistance of fetal hb

transcription

26

mutations are generally stable/unstable from generation to generation?

stable

(TNR disorders are unstable)

27

Name a paternal and maternal trinucleotide repeat disorder

1. paternal - huntingtons
2. maternal - fragile X

28

Repeat #in Huntingtons?

>40 CAG

29

Repeat# in fragile x?

>2500 CTG