Mutational mechanism of disease

Question 1

4 major mechanisms of genetic mutations that can lead to disease

Answer 1

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

Question 2

Duchenne muscular dystrophy

-affects what gene, resulting in what?

Answer 2

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

-loss of function

Question 3

What type of inheritance pattern is Duchennes MD?

Answer 3

X linked recessive

Question 4

Clinical signs of DMD?

Answer 4

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

Question 5

Hereditary neuropathy w/ liability to pressure palsis (HNPP)

-affects what gene, resulting in what? reciprocal of what?

Answer 5

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

loss in function (recip of CMT)

Question 6

What type of inheritance pattern is HNPP?

Answer 6

Autosomal dominant

Question 7

Clinical signs of HNPP?

Answer 7

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.

Question 8

Osteogenesis Imperfecta Type I

• what gene is affected?
• resulting in what?

Answer 8

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

Question 9

What type of inheritance pattern is Osteogenesis Imperfecta Type I

Answer 9

autosomal dominant

Question 10

Osteogenesis Imperfecta Type I

clinical signs

Answer 10

brittle bones
blue sclera
normal stature
progressive hearing loss in adults

Question 11

hereditary retinoblastoma

affects what gene?

Answer 11

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

• loss of function

Question 12

hemoglobin kempsey

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

Answer 12

affects beta hemoglobin gene with a Asp99Asn missense mut.,

leading to Hb molecule with higher than normal oxygen affinity

-gain of function

Question 13

alheimer’s disease in trisomy 21

has what ch mut? leading to what?

Answer 13

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

-early onset alz

Question 14

Charcot-marie-tooth (type 1A)

mut in what gene? leading to what? reciprocal of what?

Answer 14

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

-gain of funct (reciprocal of HNPP)

Question 15

Sickle cell anemia

-mut in what gene? result in what?

Answer 15

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

Question 16

Huntington’s disease

repeat of what? resulting in what?

Answer 16

• CAG (glutamine)
• toxic effect on Ht protein

-novel mut

Question 17

Osteogenesis Imperfecta type II, III, IV

Mut in what? resulting in what?

Answer 17

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

Question 18

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

Answer 18

altered expression mutation (ectopic=wrong place)

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

Question 19

hereditary persistance of fetal hb

mut in what? resulting in what?

Answer 19

deletion of genes on beta Hb locus,

resulting in retention of fetal gamma gene.

Question 20

Mechanism of hereditary persistance of fetal hb

Answer 20

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

Question 21

8 steps at which mutation can disrupt product of normal protein

Answer 21

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

Question 22

Name which step the mutation is disrupting:

- familial hypercholesterolemia

Answer 22

subcellular localization of polypeptide of holomer

Question 23

Name which step the mutation is disrupting:

-hemoglobinopathies (hammersmith)

Answer 23

polypeptide folding

Question 24

Name which step the mutation is disrupting:

Hb kempsey

Answer 24

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

Question 25

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

Answer 25

transcription

Question 26

mutations are generally stable/unstable from generation to generation?

Answer 26

stable

TNR disorders are unstable

Question 27

Name a paternal and maternal trinucleotide repeat disorder

Answer 27

1. paternal - huntingtons

2. maternal - fragile X

Question 28

Repeat #in Huntingtons?

Answer 28

> 40 CAG

Question 29

Repeat# in fragile x?

Answer 29

> 2500 CTG