Brainscape's Knowledge GenomeTM


Top Flashcards (Certified)
All Flashcards

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
transcriptional regulation
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
26
haemoglobinopathies
normal quantities of globins that have abnormal sequences causes globin chain polymerisation and misshapen RBCs e.g. sickle cell disease due to mutation
27
thalassemias
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
28
sickle cell anaemia cause what does it result in
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
29
genotypes of sickle cell
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)
30
how to diagnose sickle cell
Hb electrophoresis based on differing charge of the different Hb tetramers and their differing migration patterns in an electric field
31
thalassaemias
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
32
gene for β globulin
HBB on chr 11 2 copies expressed - 1 on each chr
33
2 types of β-thalassaemia
MINOR heterozygous mutation 1 defective gene copy MAJOR homozygous/compound heterozygous mutations both gene copies defective
34
how many HBB variants have been described where are there problems
transcription (promoter) processing of mRNA translation of mature mRNA post-translation integrity of β globin
35
β-thalassaemia minor (β-thal trait) 2 types genotypes symptoms
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
β-thalassaemia major
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
genes for α globulins
Hbα1 Hbα2 on chr 16 all 4 copies expressed - 2 on each chr
38
4 types of α-thalassaemia
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
α+ thalassaemia
1 defective locus α-thalassaemia minima or silent carrier clinically asymptomatic
40
α0-thalassaemia
2 defective loci α-thalassaemia minor/trait often clinically asymptomatic but mild cryptic symptoms mild hypochromic microcytosis mild anaemia
41
α thalassaemia trait - asian/mediterranean vs african populations
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
severe α-thalassaemias - HbH disease
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
severe α-thalassaemias - α-thalassaemia major
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
things to remember
45
learning outcomes
46
which of the following blood types are least likely for parents of a girl with blood type O
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
production of DNA
48
DNA → protein
49
mutation
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
classifications of mutations (5)
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
3 functional consequences of mutations
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
2 categories of silent mutations
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
amorph 1. effect on normal function 2. heteroxygote pattern 3. example
1. complete loss 2. recessive but dominant if haploinsufficient 3. O blood type allele
54
hypomorph (reduced) 1. effect on normal function 2. heteroxygote pattern 3. example
1. partial loss 2. recessive but dominant if haploinsufficient 3. CFTR mutations in CF
55
hypermorph 1. effect on normal function 2. heteroxygote pattern 3. example
1. increased 2. dominant 3. EGFR oncogene in cancer
56
antimorph (dominant negative) 1. effect on normal function 2. heteroxygote pattern 3. example
1. antagonistic 2. dominant 3. FBN1 mutations in Marfan syndrome (Proteins that function in a mixed multimer - Collagen network can't form)
57
neomorph 1. effect on normal function 2. heterozygote pattern 3. example
1. different/new 2. dominant 3. BCR-ABL fusion protein in CML
58
isomorph (silent)
no effect on normal function no heterozygote pattern
59
haploinsufficient
a single copy of wild-type allele is not sufficient for normal phenotype
60
Hypomorph - reduced function - Hb does form a mixed multimorph, this 1 is NOT INHERITED IN A DOMINANT FASHION
61
Neomorph - fusion protein - new function - dominant If it's a fusion protein it is more than likely neomorph
62
case description of sickle cell anaemia
63
acute chest syndrome
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
sickle cell prenatal diagnosis
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
sickle cell screening
isoelectric screening certain at risk mothers are screened
66
why is sickle cell anaemia incidence lower in African Americans than in Africans
Evolutionary pressure on Africans to inherit this because it protects them from malaria
67
evolution
pop. genetics - change in freq of an allele in a population over time
68
adaptation
a heritable trait that aids the survival and reproduction of an organism in its current environment
69
polymorphism
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
height is
NOT a polymorphism
71
balanced genetic polymorphism
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
HbAS sickle cell trait
confers partial resistance to malaria
73
sickle cell and balanced genetic polymorphism
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
sickle cell anaemia
HbSS character/trait clinically manifest phenotype pattern of inheritance is recessive usually parents do not have sickle cell anaemia
75
sickle cell trait
HbAS different character/trait cryptic phenotype pattern of inheritance is dominant parent almost always has HbAS
76
genetic context and thalassaemias
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
β globin gene mutations associated with β-thalassaemia
78
gene associated with β thalassaemias
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
β thalassaemias and LCR deletions
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
prenatal diagnosis of β thalassaemia
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
abnormal face shape - β thalassaemia
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
things to remember

GGE (33 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2025 Bold Learning Solutions. Terms and Conditions