Genetic diseases Flashcards
What does low penetrance of a genetic variant imply?
Only a few patients with the gene have a phenoytpe associated with that gene.
How large in base pairs does an insertion need to be to be considered a copy number variant?
> 50 base pairs
What is a nonsense variant?
One that introduces a stop codon
What is a frame shift variant?
An insertion or deletion that shifts the codon reading frame
What is nonsense decay?
Describes that destruction of RNA due to the presence of a nonsense variant.
What is a missense variant?
One that causes the insertion of different residue in the protein, which may lead to misfunction
What is a splice altering coding variant?
Variant that causes a change to specific splicing marker on the RNA, leading to it being incorrectly spliced and the resultant protein being dysfunctional.
How are metabolic conditions usually inherited?
Autosomal recessive. This is because the there is usually redundancy for the production of enzymes involved in metabolic function, and one copy of the gene is usually adequat to prevent disease.
Why is it that negative autosomal dominant diseases exist?
They exist where the proteins that are produced by the health and vairant DNA need to work together to acheive their function. An example is osteogenesis imperfecta where the affected colagen gene prodcues proteins that need to make a triple helix with the healthy collagen gene, leading to no functional collagen.
What is male and female drawn as in a pedigree?
Circle is female. Square is male.
What’s the diferenec between variabel expression and incomplete penetrence?
Variable expression means that all those with the effected gene (s) show the phonetype with varying degrees of severity, but incomplete penetrance means that only some gene variant affected infdividuals will have no evidence of the disease.
What is gonadal mosacisim?
When the parents gonadal cells have a mutation that the other cells of their body do not.
What is somatic mosacisim?
Where some of the cells in a person have variant, but other cells do not.
What is pseudodominance?
It’s where the carrier frequency is so common that a truly autosomal recessive disease appears autosomal dominant.
Why might you only see an X-linked condition in females? E.g. Rett sydnrome.
When the condition is lethal in males.
Where the condution is Turner Syndrome.
Note that X-inactivation may lead to females having an X-linked disease phenotype, but males will have this as well.
What is anticipation?
It’s the slowly increasing severity of the phenotype as the generation number increases.
Heteroplasmy is important for mitochondiral disease. What is this, why is it important?
The number of mitochondria with mutations is the defining factor that will influence the likelihood disease.
What are the three survivable autosomal aneuplodies?
21, 18 (edwards), 13 (Patau)
What is non-disjunction in meiosis?
The failure for chromatid pairs to separate, leading to double the genetic material being left in the daughter cell, causing aneuploides.
Segmental aneuploides have have what type of inheritence?
Autosomal dominant
What is a point mutation?
Single change in a base pair
What is a point mutation referred to if it changes the amino acid sequence?
A missense mutation.
If a missense mutation results in an amino acid change for a new amino acid of similar biochemical properties, it is referred to as what?
A conservative missense mutation. If the new amino acid is biochemically very different is is called a ‘non-conservative’ missense mutation.
What DNA change occurs in sickle cell anaemia?
Nucleotide triplet in the beta-globin chain in haemoglobin is changed from CTC to CAC, which causes a glutamate to valine switch. This causes misfolding of beta-globin, haemoglobin, and a deformed resulting cell.
What are the two bases that seem to appear in trinucleotide repeats with great frequency?
Cytosine and guanine.
What is the gene called that has CGG repeats in it and leads to fragile X-syndrome if the there are too many repeats?
Familial mental retardation 1 (FMR1)
What’s a nonsense mutation?
Introduction of a stop codon
What is difference between the word hereditary and congenital?
Hereditary means obtained from ones parents. The word congenital means born with. So huntington’s disease is hereditary but not congenital, and congenital syphillis is congenital but not hereditary.
If a single gene leads to multiple effects- what is this referred to?
Pleiotropism
What is called when multiple gene defects producing the same phenotypic outcome?
Genetic heterogeneity
How does variable expressivity differ from penetrance?
Variable expressivity describes traits that different but attributable to the same dominant mutation. Penetrence refers to the degree to which the one trait is expressed as the result of a dominant mutation.
What does the term - dominant negative - allele mean?
It infers that not only is the resultant gene non-functional, that it also interferes with the function of normal genes. E.g. one mutated collagen chains leads to dysfunction of the other two as collagen needs to be a trimer to function.
What do Huntington disease, neurofibromatosis, myotonic dystrophy, tuberous sclerosis, polycystic kidney disease, familial polposis coli, hereditary spherocytosis, von willebrand disease, marfan syndrome, EDS, osteogenesis imperfecta, achondroplasia, familial hypercholsterolaemia, and acute intermittent porphyria all have in common?
Autosomal dominant conditions
Is incomplete penetrence more common in autosomal dominant or recessive disorders?
Autosomal dominant.
There is usually comoplete penetrence when the two defective (autosomal recessive) genes are present.
Inherited enzyme mutations tend to produce diseases with dominant or recessive inheritence?
Recessive
- in their hetrozygous form, recessive enzyme deficiencies are clinically silent because the normal gene makes enough enzyme to complete the physiological role of that enzyme.
What is the best explination for the absence of Y-linked inheritence?
Almost all the genes specific to the Y chromosome are involved in spermatogenesis. Mutations causing dysfunction here lead to infertility, and so cannot be inherited.
How is glucose-6-phosphate dehydrogenase deficiency (G6PD) inherited?
X-linked.
How do you explain females expressing traits associated with X-linked diseases?
Either homozygotes for the gene, or more likely, have a degree of X-inactivation leading to expression of the mutant allele.
What do haemophilia A/B, Duchenne muscular dystrophy, agammaglobulinaemia, Wiskott-aldrich syndreom, diabetes insipidus, LEsch-Nyhan syndreom and Fragile X syndrome all have in common?
All X-linked
What’s special about vitamin D-resistant rickets and Alport syndrome?
The are both X-linked DOMINANT, conditions. X-linked conditions are almost always recessive.
What do thalasaemias, osteogenesis imperfecta, hereditary spherocytosis and muscular dystrophies have in common?
All caused by inherited mutations that cause defective STRUCTURAL proteins.
What gene is mutated in Marfan syndrome? How does it cause disease?
The fibrillin-1 gene FBN1.
Fibrillin-1, along with FBN2, are key components of microfibrils found in the ECM. When defective, the ECM is weak. This is problematic for connective tissues in the lens, the large arteries, the heart. Furthermore, TGF-beta availability is governed by microfibrills. In the presence of functional fibrillin-1 containing microfibrils, TGF-beta is sequestered in the ECM, and only available on injury to facilitate repair. In Marfan’s, the TFG-beta is more available and leads to inflammatory and ECM augmenting activity that adds to derfomity of structures (e.g. the mitral valve) in Marfan’s disease.
What is Marfan’s syndrome type 2?
It’s the phenotype of Marfan’s that involves mutations in TGF-beta type 2 receptor that prevent it being sequestered, and allow it to be overactive as is seen in Marfan’s syndromem type 1.
What are the morphological, syndromic, features of patient’s with Marfan’s syndrome?
Tall
Long extremites compared to height
Tapering fingers and toes
Long headed (dolichocephalic)
Bossing of the bones of the face, particularly the supraorbital ridge
Kyphosis or scoliosis
Slipping of the dorsal or lumbar vertebrae
Chest deformity (excavatum or cavinatum)
What is the ocular disease that is almost only seen in patients with Marfan syndrome?
Ectopia lentis - the subluxation or dislocation (usually upward and outward) of the lens.
It is due weakening of the ciliary zonules (the fibrous structures the hold and pull on the lens)
What are the two most prevalent cardiovascular abnormalities affecting patient’s with Marfan’s disease?
Mitral valve prolapse (40-50% of patients), and dilation of the ascending aorta due to cystic medionecrosis (necrosis of the media of the aorta) +/- aortic dissection.
What is the mechanism of mitral valve porlapse in Marfan’s syndrome?
Defective microfibrils make up the cordae tendinae of the mitral valve. They become lax, leading to prolapse +/- regurgitation. Note that similar things can occur to the tricuspid valve, and rarely the aortic valve.
What are the subcategories of EDS?
Classic
Hypermobile (no genetic association)
Vascular
Kyphoscoliosis (most common)
Arthrochalasia
Dermatosparaxis
What do the vascular EDS subtypes result from?
Mutations in genes effecting the production of type III collagen.
What type of collagen is typically effected in classical EDS?
Type V collagen (usually defects in COL5A1/2)
Familial hypercholesterolaemia is caused by defects in what gene?
The gene encoding the low-densisity lipoprotein receptor (most common - about 85% of cases). A minority of cases are caused by apolipoprotein B-100 (the ligand for the LDL receptor in the LDL particles) affecting 5-10% of cases, and gain of function mutations in proprotein convertase subtilisin/kexin typ 9 (1-2% of cases) - PCSK9.
How does LDL-receptor dysfuntion lead to the phonetype seen in familial hypercholesterolaemia?
LDL receptor is responsible for binding to LDL/apoliporprotein B particles and removing them from circulation. This lowers circulating cholesterol and reduces the likelihood of the formation of atheromas.
What is the role of PCSK9 in normal people?
It regulates the expression of LDL-receptors. When active PCSK9 causes LDL receptor recycling and reduces it’s ability to sequester LDL cholesterol from the circulation. PCSK9 inhibitors therfore enable the LDL receptors to function for longer and clear more cholesterol.
Outgoing cholesterol carrying particles from the liver, after initial acquistion of cholesterol from the gut as chylomicrons, is in what form?
Very low densisity lipoprotein - more triglyceride and proteain (Apo B/C/E) than LDL.
What happens to VLDL particles (with ApoC, B, E in situ) when it reaches its target tissue (e.g. muscles, adipose, solid organ)?
It undergoes lipolysis and the remanent intermediate-density lipoprotein goes into circulation. ApoC is lost in the process. ApoB and E remain.
What happens to the remanent Intermediate-density lipoprotein (IDL), the waste product after VLDL is used in tissue?
About 50% is taken up by LDL receptor (binds to ApoB/E, so also called the ApoB/E receptor) mediated transport into the liver for recycling back into VLDL. The remainder then is processed further by target tissues into LDL. The ApoE is lost, and most of the triglyerides are gone by this point.
In triglyceride and cholesterol trafficking to and from the liver, VLDL becomes IDL beomces LDL. What happens to the ratio of cholesterol to triglycerides accross this journey? What happens do the protein components of these molecules?
Triglycerides:Cholesterol ratio decreases from VLDL -> IDL -> LDL. So to do the surface proteins Apo B/C/E -> ApoB/E -> ApoB
IDL and LDL binding to LDL-receptors (binding ApoB/E or just ApoB respectively) leads to update of the lipids into a lysosome. How does the cholesterol escape the lysosome?
Two proteins facillitate the transfer NPC1 and NPC2.
What action does have cholesterol have in hepatocytes after being brought in as LDL/IDL and escaping the lysosome?
Suppresses furthre cholesterol synthesis by inhbition of HMG CoA
Activates acyl-coenzyme:cholesterol acyltransferase - this favours esterification and storage of excess cholesterol
Suppresses the synthesis of LDL receptors, thus protecting the cell from excess LDL uptake that could lead to steatosis.
Upregulartes expression of PCSK9, which further reduces the LDL receptor recycling and leads to their destruction.
Like CF, familial hypercholesterolaemia can be due to different parts of LDL gene of to genes that effect its processingl. How the LDL receptor malfunctions is classified as class I through VI. What do the classes represent?
Class I - failure to synthesis LDLR
Class II - failure to transport LDLR out of the ER
Class III - failure of LDLR to bind LDL or IDL properly
Class IV - failure to cluster around clathrin coated pits so can’t endocytose.
Class V - failure to be able to be recycled
Class VI - failure to localise to the basolateral hepatocyte membrane
How do HMG-CoA receptors work to lower serum cholesterol?
They reduce intra-hepatocyte cholesterol synthesis, which in turn increases the number of LDL receptors on the basolateral surface of hepatocytes, increasing the ability to remove plasma LDL and IDL.
How do organelles receive the intra-organelle proteins they need?
They get them from lysosomes that are formed and then fuse with the organelle, dropping off the needed proteins.
What is the significance of mannose-6-phosphate groups being attached to the terminal ends of proteins processed in the golgi apparatus?
Binding of mannose-6-phosphate groups serves as an ‘address’ label recognised by specific resceptors found on the inner membrane of the golgi. Lysosomal enzymes now with their M6P groups bind these receptors and are then sequestered from the other secretary proteins being produced in the golgi. Small vessicles take these lysosomal enzymes to fuse with and deliver them to lysosomes.
Defects in lysosomal enzymes can lead to accumulation of their unprocessed or partially processed substrate. What happens to cells full of lysosomes with undigested substrate?
The lysosomes are unable to perform their critical cell homeostasis roles. Noteably they are unable to fuse with the autphagosomse to perform autophagy, and especially mitophagy (recycling of mitochondria). This leads to accumulation of inefficient and leaky mitochondria, which are inefficient at making ATP, produce reactive O2 species, and can trigger intrinsic apoptosis. Accumulation of other protein products is also slowed leading to accumulation of damaging substances such as alpha-synuclein and Huntingtin.
In Tay-Sachs disease, what enzyme is missing?
hexominidase A
The missing enzyme in Tay-Sachs disease is hexominidase. What does this enzyme do?
It usually degrades ganglosides - lipid/carbohydrate structures. The particular class of langliosides degraded by hexaminidase is called GM2. The disesae phenotype is the result of accumulation of this substance, and is so also called GM2 gangliosidosis.
What is different in appearance about Gaucher cells (glucocerebroside accumulation) compared to other affected lysosomal storage disease cells?
Rather than vacuolated, fibrillary type cytoplasms that loos like crumpled tissue paper.
What is meant by a paracentric or pericentric inversion (with regards to karyotyping)?
Paracentric invesrsion refers to 2 breaks occuring on one end of a chromosome cleaving a piece of genetic material that doesn’t include the centromere. This is flipped and then re-inserted into the same gap in the chromosome.
Peri-centric inversion is the same, but the breaks are on either side of the centromere, and the inverted material involves the centromere.
What is an isochrome?
Sometiems, the long or short arm is lost. This results in duplication of the remaining arm, which new chromosome forming with 2 of the same arm about the centromere (either two short or 2 long arms). One compatible with life is i(X)(q10), where only the long arm of X is present, twice.
In a balanced translocation, no genetic material is lost as part of one chromosome swaps places with part of another chromosome. Why can these still be prolematice?
When gamete production occurs, some of the gametes will likely be left with insufficient genetic material from one of the chromosomes and too much from the other.
What leads to a robertsonian translocation?
Breaks on either side but near the centromere of 2 acrocentric chromosomes. The small centre pieces fuse and is usually lost. The long remaining pieices als fuse, greating a big long chromosome.
