3. Genetics and disease 2 - Monogenic disorders Flashcards
what are monogenic disorders?
disorders caused by defects in a single gene
this makes them reasonably straightforward to study
what types of mutations result in monogenic disorders?
loss of function mutations like in Hirschsprung disease
gain of function mutations like in cancers (multiple endocrine neoplasia)
what do monogenic disorders follow?
simple Mendelian inheritance so it is quite easy to identify the genotype based on the phenotype
what is penetrance?
the proportion of the population with a particular genotype presents the phenotype in individuals in a population
100% penetrance = everyone with the genotype has the disease
what is complete penetrance?
100% of a genotype show the associated trait
what is imcomplete penetrance?
<100% of a genotype show the associated trait
why might a genotype not show the phenotype?
due to environmental influences
what is an example of incomplete penetrance?
BRCA1/2 genes
you can have the gene without getting the cancer
what is an autosomal dominant disorder?
- the dominant allele has the mutation
- only 1 allele needs to be affected to show the phenotype
- both sexes are affected
- they are often traceable through many generations
- affects heterozygous individuals for the abnormal allele
- 50% of offsring affected
- usually gain of function mutations
what are examples of autosomal dominant disorders?
huntingtions disease
hereditary rentinobastoma
achondroplasia
what can make identifying autosomal dominant disorders harder?
- Pleiotropy
- reduced penetrance
- variable expressivity
- new mutations
- co-dominance
- homozgosity
what is pleiotropy?
a single gene defect causes multiple disease phenotypes that appear unrelated but they are
what is reduced penetrance?
when there are no clinical features despite carrying a mutation
what is variable expressivity?
the range of variation in the clinical presenting phenotype in affected individuals
what are new mutations?
cases with no family history of the disorder
De novo mutations
what is co-dominance?
2 allelic traits that are both expressed in heterozygous individuals like AB blood groups
what is homozygosity?
individuals with both alleles the dominant mutation
rare but gives a more severe phenotype
what are autosomal recessive disorders?
- the recessive allele has the mutation
- affects both sexes
- often skips generations due to recessive nature
- affected individuals are homozygous for the abnormal allele
- Usually loss of function mutations
- the offspring of 2 carriers will be
- 25% affected
- 25% unaffected
- 50% carriers
what can make identifying autosomal recessive disorders harder?
- Consanguinity
- psuedodominance
- locus heterogeneity
- alleic heterogeneity
- heterozygote advantage
what is consanguinity?
having related ancestors/parents
common in inbred communities
pick up lots of mutations that cannot be disguised by injection of new alleles
what is psuedodominance?
inheritance of a recessive trait mimics dominant inheritance usually due to loss or mutation of the dominant allele
what is locus heterogeneity?
the presnce of multiple different genetic loci that cause the same/similar phenotype
different defects cause the same result and same disease
what is allelic heterogeneity?
different alleles at one gene locus that can cause the same phenotype.
the affected individual can carry 2 different alleles and express disease = compound heterozygotes
example
different mutations in the same proteins cause the same disease
what is a compound heterozygote ?
an individual carries two different mutations at a particular gene, one on each chromosome, together they cause an autosomal recessive trait
what is heterozygote advantage?
the carriers have a survival advantage so the genotype is enriched in the population
like sickle cell disease and malaria
what are X-linked recessive disorders?
- mutant allele is on a X chromosome
- often traceable through generations
- affected males are hemizygous for the abnormal allele
- loss of function mutations
- offspring of a female carrier
- 50% sons affected
- 50% daughter carriers
what are examples of X- linked recessive disorders?
duchenne muscular dystrophy
haemophillia A and B
why does variable expression in heterozygous females make X-linked disorders harder to study?
the 2nd X undergoes random gene silencing to prevent over expression
this gives a mosaic phenotype
what causes of affected females with X-linked disorders harder to study?
- homozygosity for an X linked recessive disorder
- skewed X- inactivation that is not random and driven by gene expression
- numerical X chromosome abnormalities like XO which means the phenotype is expressed
- X-autosome translocations
- Translocations within the X
what are X-linked dominant disorders?
affect hemizygous males and heterozygous females
excess of affects females in families
what is Y linked inheritance?
hairy ears?
any disorder to do with spermatogenesis
what is Partial sex linkage?
when psuedoautosomal X genes escape X inactivation
what is sex influence disorders?
hormonal effects like male pattern baldness
virillisation in females with congenital adrenal hyperplasia
what are pseudoautosomal genes?
- they exist in the psuedoautosomal regions of the X and Y chromosomes
- these regions recombine during meiosis
3a. Partially sex-linked loci are on both sex chromosomes so they are diploid
3b. they follow autosomal patterns of inheritance but males pass on X to daughters and Y to sons - they escape X in activation
what is the Hardy- Weinberg principle?
both allele and genotype frequencies in a population remain constant from generation to generation unless specific disturbing influences are introduced
it is an ideal state that provides a baseline against which change can be analysed
what are some things that disturb the ideal state in the hardy-weinberg principle?
non random mating
inbreding
mutations
selection
random genetic drift
gene flow
what is genetic flow?
a new influx of genes to the population
allele frequency
allele A = frequency p
allele a = frequency q
p+q=1 (100%)
genotype frequency
AA = p^2
aa = q^2
Aa = 2pq
p^2 +2pq+q^2 = 1 (100%)
what is cystic fibrosis?
- autosomal recessive
- CFTR gene that encodes cystic fibrosis transmembrane regulator
- incidence 1/2000 carriers 1/22
- defective secretory systems part of innate immunity
- thick mucus, trapped bacteria, chronic lung disease, pancreatic failure, premature death
- Symptom severity can depend on the mutation of the combo of mutations
CFTR genetic info
250KB
27 exons
6.5Kb mRNA
1480 aa protein
cystic fibrosis transmembrane regulator protein function
mucosal transmemrbane protein
chlroide channel with ATP binding site
Cl- leaves the cell and water follows which helps with secretions
CFTR mutations
F508 = phenylalanine deletion that causes a protein folding defect, leading to degradation and reduce surface expression
>60 other mutation sites
CFTR advantage
thought to be protective against S. Typhi as it uses the protein to enter the cells
what is duchenne muscular dystrophy (DMD)?
- X-linked recessive
- DMD gene
- encodes dystrophin
- Incidence = 1/4000
- usually causes death before 30
- affects girl with translocation through Xp21
- affects boys with other abnormalities in Xp21
DMD gene
2000Kb
>65 exons
16Kb mRNA
3685 amino acid protein
DMD protein Function
427kD
common features with muscle structural proteins
links actin to a protein complex in the plasma membrane
DMD mutations
large deletions = absent/truncated protein = severe disease
small deletions = partly truncated protein = mild disease
what is Huntingtons disease?
- autosomal dominant
- HTT gene
- protein huntingtin
- very rare = incidence 1/37000
- all cases in the US can be traced back to 2 brothers
- progressive neurological condition with loss of coordination
- late onset
HTT gene
one of the first maped by linkage
180kb
67exons
13.7kb mRNA
(CAG)n repeats
HTT protein - huntingtin
normally 348kD
no known homology with other proteins
more repeats in disease protein
HTT mutation
- a trinucleotide repeat CAG that is normally present 16-36 times
- disease sufferes have 42-86 repeats
- the number of repeats increases through the generations
- more repeats = more severe symptoms
- called dynamic mutations
trinucleotide repeat disorders
- all have (XYZ)n
- n is increased in affected individuals
- result of founder effect mutations
- often severity of symptoms increase through generations
what are the classes of trinucleotide repeat disorders?
- fragile site
- neurodegenerative
- myotonic dystrophy
- friedrich ataxia
Fragile site diseases
All chromosomes have fragile sites where they are more likely to break at this point under cellular stress
Repeat expansion can increase the size of these fragile sites and make breakage more likely
eg fragile X
neurodegenerative trinucleotide repeat disorders
(CAG)n with n<150
multiple effects on protein protein interactions and cause toxic protein aggregates
myotonic dystrophy: trinucleotide repeat disorder
(CTG)n with n= 200-400
in the 3’ untranslated region which effects the mRNA
progressive muscle weakness and prolonged muscle contraction - myotonia
trinucleotide repeat disorder: Friedrich ataxia
(GAA)n with n =200-900
within the intron which decreases transcription
progressive damage to the nervous system
what are haemoglobinopathies?
inherited disorders of haemoglobin structure or synthesis
includes sickle cell aneamia and thalassaemia
how does haemoglobin expression change throughout your life?
- variable expression with different affinities
- foetal Hb have higher affinity to get oxygen from the mother. this stops being expressed around 40 weeks old
- adult Hb can be HbA or HbA2
- HbA2 is expressed in low levels in every RBC but we dont really know what it does but it appears to have a higher affinity then HbA
what is sickle cell disease?
- autosomal recessive
- common in endemic malaria areas
- 1/100 incidence
- ß-globin defect
- GAG to GTG
- Glu - Val
HbB to HbS - HbS is hydrophobic so forms the sickle shapes and is quite brittle causing the destruction of RBC causing anaemia
what can causes changes in the haemoglobin structure?
- point mutations
- deletions and insertions
- frameshifts
- chain termination
- fusion chain
how does the rare Hb lepore occur?
Misaligned crossing over in meiosis creating a fusion Hb protein
- usualy fine but if you have compound heterozygous with another mutation is causes disease
what are the thalassaemias?
- disorders in the synthesis of haemoglobin
- autosomal recessive
ß-thalassaemia
- lack of ß global chains
- not normally caused by gene deletions but point mutations insertions and deletions
- causes free a chains which precipitate and destroy RBC precursor
- OR causes continued production of y globin which release oxygen less readily causing bone deformity and wasting disease
alpha-thalassaemia
- deletion of a chain gene
- a1 +a2 deleted = severe disease
- a1 or a2 deleted = mild disease
- if all 4 gene deleted then death
- 3 genes deleted = variable anaemia
- 1 or 2 genes deleted = mild anaemia
deltaß-thalassaemias
- reduced synthesis of both delta and ß chains
- rare
- mild to severe anaemia
- mild form = hereditary persistance of foetal haemoglobin affecting oxygen delivery
