Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

GGE > Genetics 3 - Haemoglobinopathies and Mutation > Flashcards

Genetics 3 - Haemoglobinopathies and Mutation Flashcards

1
Q

learning outcomes

A
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

where is the H antigen located

what is it responsible for

A

H locus on chr 19 - fucosyltransferase

responsible for synthesis of a sequence of monomers (saccharides and related) on RBC surface molecules

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

what determines the ABO group

A

ABO locus chr 9

glycosyltransferase

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

codominance

A

2 alleles of the same gene which code for proteins with different specific functions are co-expressed (both alleles are expressed completely) in (compound) heterozygote individuals - rare

whereas incomplete dominance is a blending of traits, in co-dominance an additional phenotype is produced

e.g. AB blood group

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

O blood group

A

unmodified H antigen

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

A blood group

A

addition of N acetyl-galactosamine

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

B blood group

A

addition of N acetyl-glucosamine

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

AB blood group

A

addition of N acetyl-galactosamine and N acetyl-glucosamine

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

6 genotypes of ABO blood group antigen

A

homozygous

AA - A

BB - B

OO - O

heterozygous

AO - A

BO - B (O = null mutation)

AB - AB (co-dominant expression)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Hb tetramer - adults

A

2 x α globins - 141 AAs

2x non-α globins - usually β globins - 146 AAs

humans are diploid = 23 pairs of chromosomes

2 copies (often different alleles) of each gene

Hb genes have BIALLELIC EXPRESSION

both paternal and maternal alleles are expressed - both alleles need to be working for normal Hb synthesis

function = carry O2

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

β and α gene cluster - on which chromosomes

A

In order of how they are expressed from development to adulthood

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

changes in globin synthesis in embryonic development

A

https://www.youtube.com/watch?v=vhB0oNLYIqo

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

HbFF

A
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

HbA

A
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

HbA2

A
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

HbS - sickle cell anaemia

A
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

what happens to free Hb

A

catabolised and excreted (renal)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

how is Hb prevented from being lost

A

packaged in erythrocytes

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

conc of Hb in RBCs

A

320-350g/L of cytoplasm

close to limit of solubility of Hb in physiological solution

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

Hb - what is and isn’t soluble

A

globin chains (monomers) - not soluble

tetramer - highly soluble

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

what happens when Hb exceeds solubility limit

A

polymerisation and precipitation

distorted RBC shape and impaired function

RBC lysis

release of Hb

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

once transcription of globin genes is activated

A

lots of Hb is made

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

how is Hb gene expression coordinated

A

by chromatin restructuring

correct proportion of α and β chains requires co-ordinated gene expression from 2 chr

safety valve (protease) for degradation of α chains can correct some excess of α globins

  • finite capacity - easily overloaded
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

region responsible for regulation of Hb synthesis

A

LOCUS CONTROL REGION

1000s of bps upstream of β globin gene cluster

Required for expression of non-alpha globin genes and enhances expression of link genes at distal reg. sites by recruiting chromatin modifying co-activator and transcription complexes

HS - hypersensitive site

Short regions of chromatin sensitive to cleavage binding nucleases

LCR - cis acting reg. region

Encoded on same molecule it is acting on

HS 40 - cis acting - same gene structure it regulates

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Q

transcriptional regulation

A

cis acting sequences (acting from the same molecules)

⇒ act on the DNA strand on which they are encoded

do not encode for peptides

promoters/enhancers/silencers

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
26
Q

haemoglobinopathies

A

normal quantities of globins that have abnormal sequences

causes globin chain polymerisation and misshapen RBCs

e.g. sickle cell disease

due to mutation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
27
Q

thalassemias

A

normal globin chain sequences but the different chains are not in correct proportions

not enough Hb (anaemia) and/or abnormal accumulation of globin subunits (toxic)

caused by mutation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
28
Q

sickle cell anaemia cause

what does it result in

A

caused by mutation in β globin gene sequence

under conditions of low O2 tension

polymerisation of Hb

distortion of RBC shape and function

obstruction of small BVs

intravascular haemolysis

splenomegaly

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
29
Q

genotypes of sickle cell

A

codon for glutamic acid becomes a codon for valine

gene map locus 11p15.5

1 mutated allele = HbAS ⇒ sickle cell trait

2 mutated alleles = HbSS ⇒ sickle cell anaemia (no normal HbA)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
30
Q

how to diagnose sickle cell

A

Hb electrophoresis

based on differing charge of the different Hb tetramers and their differing migration patterns in an electric field

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
31
Q

thalassaemias

A

most common genetic disorders of Hb

inherited condition characterised by defects in the balanced biosynthesis of normal Hb globin chains

results in:

  1. not enough Hb (anaemia)
  2. abnormal accumulation of globin subunits
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
32
Q

gene for β globulin

A

HBB on chr 11

2 copies expressed - 1 on each chr

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
33
Q

2 types of β-thalassaemia

A

MINOR

heterozygous mutation

1 defective gene copy

MAJOR

homozygous/compound heterozygous mutations

both gene copies defective

34
Q

how many HBB variants have been described

where are there problems

A

transcription (promoter)

processing of mRNA

translation of mature mRNA

post-translation integrity of β globin

35
Q

β-thalassaemia minor (β-thal trait)

2 types

genotypes

symptoms

A

heterozygous for defective β globulin expression

either β0 (absent) or β+ (reduced)

GENOTYPES: β/β0, β/β+

clinically asymptomatic or mild symptoms

mild microcytic anaemia

small and hypochromic RBCs

36
Q

β-thalassaemia major

A

both copies of chr 11 affected

homozygous for defective β globulin expression

either β+ (reduced) or β0 (absent)

GENOTYPES:

β0/β0,

β+/β+,

β0/β+ (compound heterozygote)

serious illness requiring lifelong transfusions

37
Q

genes for α globulins

A

Hbα1

Hbα2

on chr 16

all 4 copies expressed - 2 on each chr

38
Q

4 types of α-thalassaemia

A
  1. silent carrier - 1 defective locus
  2. α-thalassaemia trait - 2 defective loci
  3. HbH disease - 3 defective loci
  4. α-thalassaemia major/HbBart - 4 defective loci ⇒ hydrops faetalis
39
Q

α+ thalassaemia

A

1 defective locus

α-thalassaemia minima or silent carrier

clinically asymptomatic

40
Q

α0-thalassaemia

A

2 defective loci

α-thalassaemia minor/trait

often clinically asymptomatic but mild cryptic symptoms

mild hypochromic microcytosis

mild anaemia

41
Q

α thalassaemia trait - asian/mediterranean vs african populations

A

A/M - common deletion of both copies of gene from 1 chr 16 (cis deletion) with 1 normal chr 16

African - 1 gene missing from each of 2 copies of chr 16 (trans deletions)

42
Q

severe α-thalassaemias - HbH disease

A

HbH disease

3 defective loci

most common in Asian heritage

need 1 chr with no α gene

β chain excess and production of HbH (4 x β globins)

43
Q

severe α-thalassaemias - α-thalassaemia major

A

HbBart

4 defective loci

hydrops faetalis

no α produced

get production of 4 γ tetramers

no O2 released to tissues and foetus dies

most often gene deletions

44
Q

things to remember

A
45
Q

learning outcomes

A
46
Q

which of the following blood types are least likely for parents of a girl with blood type O

A

AB and B

if girl is blood group O, only 1 possible genotype - OO homzygous

so she must have gotten O allele from both parents

47
Q

production of DNA

A
48
Q

DNA → protein

A
49
Q

mutation

A

permanent heritable change in nucleotide sequence of a gene or chr

change in:

genomic DNA - g.

complimentary (coding) DNA - c.

protein - p.

G > A ⇒ G change to A

50
Q

classifications of mutations (5)

A
  1. deletions
  2. insertions
  3. substitutions (missense, nonsense, splice site) - No change in number of bases - 1 base swapped out for another
  4. frameshifts - may arise from deletions or insertions
  5. dynamic mutation - tandem repeats e.g. HD
51
Q

3 functional consequences of mutations

A
  1. loss of function - inactivating - protein has no/less function - often recessive
  2. gain of function - activating - increase in normal gene function e.g. increased gene expression or different and abnormal function - usually dominant
  3. silent mutations - multiple codons for the same base - redundancy
52
Q

2 categories of silent mutations

A
  1. synonymous nucleotide change - no change in AA sequence - multiple codons for each AA
  2. non-synononymous nucleotide change - change in AA sequence that results in no change of function (AA produced is similar to the original one)
53
Q

amorph

  1. effect on normal function
  2. heteroxygote pattern
  3. example
A
  1. complete loss
  2. recessive but dominant if haploinsufficient
  3. O blood type allele
54
Q

hypomorph (reduced)

  1. effect on normal function
  2. heteroxygote pattern
  3. example
A
  1. partial loss
  2. recessive but dominant if haploinsufficient
  3. CFTR mutations in CF
55
Q

hypermorph

  1. effect on normal function
  2. heteroxygote pattern
  3. example
A
  1. increased
  2. dominant
  3. EGFR oncogene in cancer
56
Q

antimorph (dominant negative)

  1. effect on normal function
  2. heteroxygote pattern
  3. example
A
  1. antagonistic
  2. dominant
  3. FBN1 mutations in Marfan syndrome (Proteins that function in a mixed multimer - Collagen network can’t form)
57
Q

neomorph

  1. effect on normal function
  2. heterozygote pattern
  3. example
A
  1. different/new
  2. dominant
  3. BCR-ABL fusion protein in CML
58
Q

isomorph (silent)

A

no effect on normal function

no heterozygote pattern

59
Q

haploinsufficient

A

a single copy of wild-type allele is not sufficient for normal phenotype

60
Q
A

Hypomorph - reduced function - Hb does form a mixed multimorph, this 1 is NOT INHERITED IN A DOMINANT FASHION

61
Q
A

Neomorph - fusion protein - new function - dominant

If it’s a fusion protein it is more than likely neomorph

62
Q

case description of sickle cell anaemia

A
63
Q

acute chest syndrome

A

sickle cell crisis

chronic pain

organ damage

swelling in hands and feet

bacterial infections

autosplenectomy by mid-childhood

require immunisation against common pathogens and prophylactic ABs

64
Q

sickle cell prenatal diagnosis

A

chorionic villous sampling (9-10 weeks)

PCR amplify fragment of β globin gene

oligonucleotide probe hybridisation/sequencing

can also do amniocentesis - need to grow cells in lab first to do PCR

65
Q

sickle cell screening

A

isoelectric screening

certain at risk mothers are screened

66
Q

why is sickle cell anaemia incidence lower in African Americans than in Africans

A

Evolutionary pressure on Africans to inherit this because it protects them from malaria

67
Q

evolution

A

pop. genetics - change in freq of an allele in a population over time

68
Q

adaptation

A

a heritable trait that aids the survival and reproduction of an organism in its current environment

69
Q

polymorphism

A

2 or more discontinuous (different) forms occur in a single population in the same place at the same time

single (panmitic) population means random (unrestricted) mating within the group

70
Q

height is

A

NOT a polymorphism

71
Q

balanced genetic polymorphism

A

simultaneous occurence in the same pop. of 2+ “discontinuous” genetic forms in “such proportions” that the frequency of occurence of the rarest of them cannot be explained just by recurrent mutation or immigration

such proportions = freq of at least 1% of alleles

something in the environment is acting to select for maintenance of equilibrium (balance) between the different forms in the population

i.e. natural selection

72
Q

HbAS sickle cell trait

A

confers partial resistance to malaria

73
Q

sickle cell and balanced genetic polymorphism

A

HbSS (sickle cell disease) = an inevitable consequence of selection pressure for the maintenance of the heterozygous state

if the heteroZ state was not advantageous you would expect the extinction of HbSS by -ve selection

74
Q

sickle cell anaemia

A

HbSS

character/trait

clinically manifest phenotype

pattern of inheritance is recessive

usually parents do not have sickle cell anaemia

75
Q

sickle cell trait

A

HbAS

different character/trait

cryptic phenotype

pattern of inheritance is dominant

parent almost always has HbAS

76
Q

genetic context and thalassaemias

A

a specific β globin allele associated with different phenotype

depending on co-inherited modifying factors

level of expression of HbF

level of expression of α globin

* Sequence of globin genes is correct - Proportion being produced - imbalance

77
Q

β globin gene mutations associated with β-thalassaemia

A
78
Q

gene associated with β thalassaemias

A

HBB gene promoter - where transcription machinery binds

position is normally A

nutation A-G = no binding and no transcription

common in black people with thalassaemia

also occurs in chinese people with thalassaemia

disease associated with the point mutation differs in different ethnic groups

differences in ability to compensate by synthesis of HbF in response to erythroid stress

79
Q

β thalassaemias and LCR deletions

A

genes may be fine but regulation of gene expression is critical to function LCR deletions

β globin gene is structurally normal

DNA sequence is normal for 500 bp 5’ to 3’

large 5’ deletion

far less β globin produced (no enhancer)

80
Q

prenatal diagnosis of β thalassaemia

A

Hb electrophoresis of parent’s blood first

then CVS or amniocentesis and PCR

blood of baby won’t work

not expressing β globin to sufficient levels for clear delineation of hetero/homoxygous

81
Q

abnormal face shape - β thalassaemia

A

physiological response that represents an effort to compensate for the physiological deficit associated with the inherited mutation

hypoxia - high EPO - bone marrow hyperplasia

increased haematopoiesis distorts bones

82
Q

things to remember

A

GGE (33 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions