Ch. 11 Principals of Molecular Disease; Lessons from the Hemoglobinopathies

Question 1

What type of mutation may be due to nucleotide deletions, insertions or rearrangements?

Answer 1

Loss of Function mutations.

Question 2

Disease due to DELETION of a-globin genes

Answer 2

a- Thalassemia

Question 3

Group of hemoglobinopathies which result from a reduction in the abundance of B globin

Answer 3

b-Thalassemias

Question 4

A missense mutation which will LOCK hemoglobin in its HIGH Oxygen affinity state (aka GAIN of Function Mutation)

Answer 4

Hemoglobin Kempsey

Question 5

An example of a disease which has a Novel Property mutation- in this case - due to an AA substitution

Answer 5

Sickle cell disease

Question 6

Name an example of a disease a novel property mutation due to AA substitution- in which Hemoglobin chains aggregate when deoxygenated and form polymeric fibers, which will deform RBC’s

Answer 6

Sickle Cell Disease

Question 7

Which region of mutation are associated with Structurally Abnormal Proteins- which have a loss or gain of function or a NOVEL property that causes the disease?

Answer 7

Mutations in the coding regions.

Question 8

What are the 2 general types of mutations in non-coding sequences?

Answer 8

1. those that alter the stability or splicing of the mRNA and 2. those that disrupt regulatory elements or change gene dosage.

Question 9

Which type of mutations can decrease the amount of the protein produced?

Answer 9

Both. Mutations in the coding region or in the regulatory region can each yield a decreased amount of protein produced.

Question 10

Name 5 of Diseases related to mutations in the Coding region in which the protein is abnormal.

Answer 10

1 Hb Hammersmith  
2 B-Thalassemia
3. Hb Kempsey
4. Achondroplasia
5. Hb S

Question 11

There are seven focus diseases or disease types which evolve from Mutations affecting gene regulation or dosage. Which of those involves proteins of a decreased amount?

Answer 11

1. a-Thalassemia
2. Monosomies
3. Tumor -suppressor mutations.

Question 12

Name the type of mutation which evolve from those affecting gene regulation or dosage via an inapppropriate expression (wrong time, place)

Answer 12

Ectopic - occuring in an abnormal position.

Question 13

HPFH and many onocogenes are examples of mutations in which the structure is Normal ,but out of sync. What category of mutations do these belong?

Answer 13

HPFH is hereditary persistence of fetal hemoglobin and is one of the mutations from the NON CODING region which include inappropriate expression . it is generally a benign condition, because the remaining Y gene or genes remain active after birth and Hb F (a2y2) compensates for the absence of Hb A.

Question 14

What is Hemoglobin?

Answer 14

oxygen carrier in vertebrate RBC.

Question 15

what are the most common SINGLE Gene (mutation) diseases in humans?

Answer 15

Hemoglobinopathies-disorders or human hemoglobins, with WHO estimate that 5-7% of world population being carriers.

Question 16

a2B2

Answer 16

Hemoglobin A (Hb A)

Question 17

Which chromosome can a and a like chains be found?

Answer 17

Chromosome 16

Question 18

What do a1 and a2 have in common?

Answer 18

both are clustered on Chromosome 16, they are identical, a -globin mutations which cause sever disease in both fetal and postnatal life ->

Question 19

Which disease is directly related to the structure of the hemoglobin subunit?

Answer 19

Hb Hammersmith and Hb Hyde Park- both have substitutions for Phe 42 and His92 , respectively, in the B globin molecule

Question 20

Hb Hammersmith

Answer 20

Substitution for Phe42 between helix C and Helix D. Phe42 is the phenylalanine that wedges the porphyrin ring of heme into the “pocket” of the folded protein.

Question 21

Hb HYDE PARK *(Hb M)

Answer 21

His92 - knowing that each subunit has 8 helical regions (or A-H) and His92 being one of the most conserved AA, it represents the histidine to which the iron of heme is covalently linked. normally a ferrous ion can oxidize to ferric state, when this happens thes Met hemoglobin cannot reduce. causing a heterozygote to be cyanotic. what happens when an individual is homozygotic what are they? they are dead.

Question 22

An iron containing pigment that combines with oxygen->a property that allows for transport of oxygen in erythrocytes.

Answer 22

Heme

Question 23

Zeta globin

Answer 23

embryonic form of

Question 24

Name three designations of Hemoglobinopathies.

Answer 24

1 structural variants (3 clinical pheno types)

a. hemolytic anemia
b. alt. O2 transport
c. Thalassemia
2. Thalassemias
3. HRFH

Question 25

Bilirubin

Answer 25

yellow in color, breakdown product of normal heme catabolism. is excreted in bile and urine and is elevated in many diseases.

Question 26

GAG to GTG or B6 to Val represents the AA subsitution (of a novel variety) represents which diesase process?

Answer 26

Sickle cell disease. substitution of Valine for Glutamic acid, will shift to rigid (abnormal version) Hb S and a sickle shaped RBC, which under low oxygen conditions may lead to vaso - occlusion

Question 27

Sickle Cell Disease is caused by:

Answer 27

Homogosity of the mutation of a severe autosomal recessive condition. Heterozygotes will have sickle cell trait and are generally clinically normal.

Question 28

What other condition does an individual who is heterozygotic (having the sickle cell trait) have resistance to?

Answer 28

Having the Sickle cell trait will confer Heterozygotic Advantage of resistance to Malaria.

Question 29

What are the S/S of Sickle Cell disease that may present during the first 2 years of life?

Answer 29

B/C of narrow vessels and the function required for clearing defective RBC’s, spleen is often affected. Thus pt will generally present anemia, Failure to Thrive, splenomegaly, repeated infections, and dactylitis (painful swelling of hands and feet) which is caused from the occlusion of capillaries in small bones)

Question 30

Hb C (Autosomal Recessive)

Answer 30

The B chain has substitution at 6th AA from Glutamic acid to Lysine (less soluble than HbA) tends to “C” Crystallize in RBC’s causing mild hemolytic disorder.

Question 31

polycythemia

Answer 31

Increased or abnormal numbers of circulating RBC

Question 32

Hb Kempsey (B chain Asp 99 ASN) Autosomal Dominant mutation works in which way?

Answer 32

the mutation “locks” hemoglobin into the relaxed structure with a high oxygen affinity causing polycythemia (it is a GAIN of FUNCTION)

Question 33

Reversible Oxgenation

Answer 33

oxyhemoglobin undergoes reversible oxygenation because its heme iron is int he reduced or Ferrous state,

Question 34

Heinz Bodies

Answer 34

occlusions which are caused by Thalassemia which produces in excess and will precipitate. these occlusions may be damaging to the membrane and cause premature RBC destruction

Question 35

ZF deletion (rare) leads to what disease and how?

Answer 35

at 1800bp, a 1 gene is deleted and the 3’ end of the LUC7L gene, out come is that you will transcribe a mutant hybrid RNA..fusion mRNA. resulting in hypermethylation and leading to silence. so there is NO expresssion of alpha2 globin.gene. the disease is a-thalassemia

Question 36

Single base pair substitutions or POINT mutations (not deletions) lead to which type of thalassemia?

Answer 36

Beta Thalassemia

Question 37

What is the known treatment for the side effect of “treatment” for Beta Thalassemaia (major)

Answer 37

iron chelation therapy.

Question 38

For Beta Thalassemia (major), what is an alternative to a life time of transfusions?

Answer 38

Bone Marrow Transplants.

Question 39

B zero

Answer 39

with NO HbA present , B thalassemia if only 10-30% of Hb A is detectable

Question 40

Hypochromic

Answer 40

pale , less red in RBC due to reduction in hemoglobin

Question 41

What is difference between Beta Thalassemia Major and Minor?

Answer 41

Major - individuals have 2 B thalassemia alleles, if untreated, 80% of these pt will die by age 5. whereas minor is seen in carriers of ONE B thalassemia allele

Question 42

Beta Thalassemia Minor S/S?

Answer 42

have hypochromic, microcytic RBC’s and may have slight anemia

Question 43

Facies of pt with untreated B - Thalassemia?

Answer 43

chipmunk

Question 44

what is the worst thing you could do to a patient with B thalassemia with a chain inclusion bodies?

Answer 44

increase Alpha globin

Question 45

In B-Thalassemiz, What happens when an a-chain inclusion body is formed within a RBC?

Answer 45

inclusion will be removed from the RBC by reticuloendothelial cells, which leads to damage to the cell membrane , causing premature destruction of the cell.

Question 46

alpha thalassemia

Answer 46

of the two types of thalassemias, this type is more prevalent and more widely distributed. deletions

Question 47

simple beta thalassemia

Answer 47

This disease process is derived from impaired production of B globin ALONE! result of many different types of molecular abnormalities, mostly POINT mutations in the B globin gene- most will lead to a decrease in abundnce of B globin mRNA. Includes Promoter mutants, RNA splicing mutants (most common), mRNA capping or Tailing mutants, and Frameshift or nonsense mutations.

Question 48

What role do NON functional mRNAs play in causality of Beta (zero) thalassemia?

Answer 48

these Non functional mRNA’s have premature stop codons due to single NT substitution (Gln39Stop) or single base pair deletion at codon 16_> causing B (zero) Thalassemia.

Question 49

What are the 3 examples of RNA Splicing Mutations. and what makes them unique?

Answer 49

Group 1 through 4..
1. splice junction mutations
-mut. GT at 5’donor site
-mut AG at 3’ Intron acceptor site.->result in complete loss of splicing
NOTE. Cryptic spice site- when a mutation cause a need for an alt. site which can be used by the spliceosome.
2.intron mutations- leads to activated cryptic site that will compete with normal site
3. Coding seq. changes that also affect splicing (mut in ORF activates cryptic splice site in an exon)

Question 50

Complex Thalassemias

Answer 50

caused by large deletions that remove the B globin gene PLUS one or more other genes OR the LCR

Question 51

What is inevitable outcome with a deletion in the LCR (locus control region)?

Answer 51

these deletions will abrogate ($5 word) the expression of ALL genes in the B globin cluster. those deletions are responsible for multiple types of thalassemias.