Forms of Inherited Disease Flashcards
What are 3 types of genetic diseases that are inherited in different ways?
Monogenic (Mendelian)
Polygenic
Chromosomal disorders
What does congenital vs acquired mean?
Congenital = present at birth Acquired = not inherited or present at birth
What is a polymorphism?
An allele variant that is present in more than 1% of the population
What is a variant?
Any loci that has more than one possible allele within the entire population, even if in less than 1%
What are the features of a gene that undergoes Mendelian inheritance?
The gene has two copies (maternal and paternal)
The copies of the gene separate into two gametes
The copies of the gene segregate independently
What are the features of an autosomal dominantly inherited disease gene? In terms of -penetrance -expressivity -onset -gain/loss of function
Tends to have reduced penetrance
Variable expressivity
Late onset (onset after the affected individual has had children)
Usually ‘gain of function’ - only need one allele to gain function for there to be a problem
Example of an autosomal dominant condition
Huntington’s Disease
How can a loss of function mutation ever be dominant?
Haploinsufficiency
One correctly functioning allele is not enough to maintain normal function
Features of an autosomal recessively inherited gene
In terms of
-family history
-gain/loss of function
Often no family history
Can be homozygous of compound heterozygous
Usually ‘loss of function’ mutations
Example of an autosomal recessive condition
Phenylketonuria (PKU)
What does homozygous vs compound heterozygous mean?
Homozygous = Same mutation inherited from both parents
Compound heterozygous = Different mutations inherited in each allele, both cause same problem
Features of an X-linked recessive condition
No male-to-male transmission
Mainly affects males as they only have one X chromosome, female carriers less affected
Example of an X-linked recessive condition
Duchenne Muscular Dystrophy
Features of an X-linked dominant condition
Usually only found in females, as it is usually lethal in males so they do not survive
Example of an X-linked dominant condition
Rett Syndrome
Causes delayed development, autism, lack of speech, lack of ability to walk
What is X-inactivation?
Females have two X chromosomes, so one of them is inactivated, to prevent twice the amount of gene products
Which one is inactivated in random, but all descendants of that cell will have the same one inactivated
This leads to the pattern on female tortoiseshell cats
What does hemizygous mean?
One copy of a chromosome
e.g. males are hemizygous for the X chromosome
Name examples of non-mendelian inheritance
De novo mutations Mitochondrial inheritance Epigenetic inheritance Mosaicism Trinucleotide repeat disorders
What is mosaicism?
The mutation is not present in every genetically related cell
Can occur if a mutation occurs during early mitosis of a zygote
e.g. If it occurs during the first division, 50% of all cells will be affected
What is germline mosaicism vs somatic mosaicism?
Germline mosaicism = a mutation in the germline cells means that some gamtes carry the mutation and some don’t. Disease may occur in child and siblings
Somatic mosaicism = mutation arises post-fertilisation
What is mitochondrial inheritance?
Mitochondria come from the ovum, so are inherited maternally
Severity depends on if there is heteroplasmy or not
What is heteroplasmy?
The presence of more than one type of organelle genome (e.g. mitochondrial genome) in a cell
What are trinucleotide repeat disorders?
Repeats of a codon
Happens as a result of slippage during mitosis
More repeats = increased severity
Causes diseases that have anticipation
What is anticipation?
The severity of the disease increases in subsequent generations due to an increase in the number of repeats
Example of a disease that shows anticipation
Huntington’s Disease
What are epigenetics?
A modification of gene expression that is heritable
Caused by DNA methylation, histone modifications, non-coding RNAs
What is genomic imprinting?
Type of epigenetic mechanism
The pattern of gene expression depends on which parents pattern you inherit
Example of a mitochondrial inherited disease
Maternally inherited diabetes and deafness (MIDD)
Example of a disease caused by epigenetics
Prader-Willi Syndrome
Paternal inheritance
What is MODY?
- stands for
- inheritance pattern
- monogenic/polygenic?
- main symptom
Maturity Onset Diabetes of the Young Inherited form of diabetes Autosomal dominant Monogenic Not related to Type 1 or Type 2 No production of insulin OR beta cells don't release their insulin
What are the symptoms of MODY?
Early onset - usually before age 25
Usually normal body weight (BMI under 25)
Causes hyperglycaemia - easily mistaken for Type 1 or Type 2
What mutations can be the cause of MODY?
Single mutation in hepatocyte nuclear factor genes (HNF1a/1b/4a) which express GLUT1 and GLUT2 transporters
Or NEUROD1, IPF1
Or in glucokinase gene (GCK) that codes for pancreatic glucose sensor
What is the most common mutation cause for MODY?
Single base pair insertion in HNF1a
Leads to a premature stop codon
The RNA produced is subject to nonsense-mediated-decay
Leads to haploinsufficiency of HNF1a
Why is MODY often mistaken for Type 1 diabetes?
Both have no release of insulin, leading to hyperglycaemia
Both insulin-dependent
Both have early onset
Both not linked to obesity
What is the best treatment for MODY?
Sulphonylureas
K+ channel blockers, cause depolarisation of beta cells so they are more easily activated and release insulin
Why is it important to diagnose MODY?
Patients can receive treatment more suited to the underlying cause
Family members can be screened and/or watch out for symptoms
What is the other type of monogenic diabetes, and what is the cause of this?
Neonatal diabetes
Occurs in first 6 months of life
May be permanent or transient
Caused by mutations in the K+ channels on beta cells
What are the psychological issues surrounding MODY, and coming off insulin?
Patients that have been taking insulin their whole life may have built up a psychological dependence on it
May cause loss of faith in doctors/medicine if they find out their current treatment is wrong
What are the two categories of genetic testing?
Molecular genetic test = looks at nucleotide sequence
Biochemical genetic test = looks for protein abundance/activity
What are 3 methods of screening foetuses for genetic disorders?
Ultrasound
Amniocentesis
Testing foetal DNA from cells that have entered the mothers bloodstream
What can be a detrimental effect of NMD?
Sometimes, the attenuated, partially functional protein is better than having no protein at all
E.g. cystic fibrosis chloride channels
What are the 3 RNA surveillance mechanisms?
Nonsense Mediated mRNA decay
Non-stop mediated mRNA decay
No-go decay
What happens during Nonsense Mediated mRNA decay (NMD)?
When a transcript is produced with a premature stop codon in the last 30 nucleotides, it is phosphorylated by UPF1
Degrades incorrect mRNA transcripts to prevent production of harmful proteins
What happens during Non-stop mediated mRNA decay?
Detection and decay of mRNA transcripts that lack a stop codon
Can be Ski7 mediated or non-Ski7 mediated
What happens during No-go decay?
Degradation of mRNA transcripts on which the ribosome has stalled, for example due to formation of a secondary structure
What happens when there is high amounts of glucose in the blood?
Glucose uptaken into pancreatic beta cells via GLUT2 transporters
Glucose metabolised by glucokinase, producing ATP
ATP sensitive potassium channels close, causing depolarisation
VOCCs open allowing Calcium influx
Vesicles containing insulin exocytose contents
What are the effects of insulin?
Cell growth Glycogenosis Fatty acid synthesis Protein synthesis Insertion of more GLUT4 transporters into the membrane
What happens when there is low amounts of glucose in the blood?
Pancreatic alpha cells secrete glucagon
Glucagon increases glycogenolysis
Hepatocytes release glucose into blood
What determines if a premature stop codon will lead to NMD or a truncated protein?
Stop codon in last 30 nucleotides = NMD
Stop codon before last 30 nucleotides = truncated protein
What is Huntington’s disease?
- inheritance
- onset
- prevalence
- cause
- symptoms
Autosomal dominant
Middle age onset
Rare
Mutant protein becomes elongated, sticky, doesn’t fold correctly, aggregates within cells
Causes decline of motor abilities and cognitive abilities
What is Duchenne Muscular Dystrophy?
X-linked recessive
Mutation in the dystrophin protein
Dystrophin connects cytoskeleton of muscle fibre to the extracellular matrix
Causes muscle weakness and wasting
What is phenylketonuria?
No production of phenylalanine hydroxylase, so build up of phenylalanine, which is toxic
Causes learning difficulties and epilepsy
