Ciliopathies Flashcards
What are the 2 types of cilia
Motile cilia and non motile cilia which is also called primary cilia
How can you differentiate between the 2 cilia
Motile cilia are found in bundles in one cell whereas primary cilia is found sungularly in one cell
Where are motile cilia found
They are found in the ventricles of the brain, in the respiratory tract, in the female reproductive tract and in the tail of the sperm.
The function of this cilia is to beat
What is the funciton of the primary cilia
They act like an antena and are responsible for receiving signals
Where does a cilium arise from? What is the organelle called
Mother centriole
Are primary cilia non motile structure
No. They have a phenomena inside them occuring called the intraflagellar transport. This builds and maintains cilia with the help of the kinesin and dyenins motor protiens
Is there a structural difference between primary and motile cilia
Yes. Motile cilia have microtubules arranged in a 9+2 fashion. Primary cilia have just the 9 tubules in the periphery. Refer to the image
What other features are in motile cilia that allow for efficient and effective movement
There are outer dyenin arms, innder dyenin arms and central micotubule pair (accounting for the +2 microtubule fashion). Refer to the attached image.
How many primary cilia are there in each cell
Only ONE
How does the primary cilia form
It forms from the basal body which is in turn formed from the modified mother centriole
Explain the structure of a primary cilium
It is protrudes from the basal body that appears to be an electron dense region. The protrusion of that makes most of the cilium is called an axoneme.
Kinesin and IFT complex B proteins are involved in transport to the plus end of the cilium which is at the periphery. IFT complex A proteins and dyenins are involved in retrograde transport to the minus end of the cilium. See the attached diagram.
Another component which we need to know is the transition zone which serves basically as a gate and determines what goes into the cilium. It is below the axoneme and above the basal body.
What is needed by the anterograde and retrograde transport in the cilium
It is important to know that IFT A proteins complex with dyenins for retrograde transport and IFT B proteins complex with kinesins for anterograde transport. These proteins work in complexes.
What are the name of the proteins associated with ciliary gate
Nephrocystins module proteins also called the NPHP and the MKS proteins
What protein is essential for cytoplasmic transport to the ciliary bodies?
Where does this protein transports stuff from that is directed to the transition zone?
The protein involved is called the BBSome. It transports stuff from the Golgi body to the ciliary gate.
What happens when the IFT proteins are defective
When IFT B is messed up we dont have any cilia.
When IFT A is mutant, cilia is swollen at the end.
When dyenin is mutant, this is more severe and we get hyperly swollen and short cilium
When does a cilium sprout
Only in the G1 or G0 phase
When does the cilium have to disassemble
Before the cell enters mitosis
What kind of signals can cilia process, there are 5.
- Flow/movement
- Morphogenesis
- Light
- Chemical signals
- Growth factors
Generally what kind of disease can we expect when the cilia are defective in a person
Cilia are ubiquituous so we can expect a range of diseases
Name the motile ciliopathy
Primary Ciliary Dyskinesia
It is a motile cilipoathy, it doesnt have anything to do with primary cilia
What organs will be affected by PCD
Lungs, heart and sperm
What are the symptoms of PCD
- Hydrocephalus (brain cant push the spinal fluid as the cilia doesnt beat as effectively)
- Respiratory abnormalities
- Infertility
- Laterality defects like situs inversus
- Congential Heart Defects
Why does primary or non motile ciliopathies have a range of broad symptoms as compared to PCD
Primary cilia are ubiquitous
What are the 2 diseases we should know that are associated with primary ciliopathies
Polycystic Kidney Disease and Von Hippel Lindau Syndrome
What is the inheritance pattern for PKD and VHL
Autosomal recessive
Explain the symptoms of Meckel Syndrome
It consists of encephalocele, polydactyly and renal cysts
What happens in Ciliary Chondrodysplasia
You have abnormal development of the skeletal system so the ribs are narrow and we see shortened fingers and toes.
What is the most common form of chondrodysplasia
Jeune Syndrome
Are cilia associated with obesity? What are these diseases called?
These diseases are called Bardet-Biedl Syndrome and Alstorm Syndrome. These individuals cilia in the brain are effected so they experience excessive hunger
What syndrome is known for its molar tooth sign
Joubert Syndrome
What is a common symptoms of most of the ciliopathies
Renal Cyst
Explain and contrast the 2 diseases called the nephronophthisis and polycystic kidney disease
In nephronophthisis the cilia are defective which can be seen at a structural level (the cilia appear shorter and disorganized). This leads to fibrosis in the kidney.
In PKD, the genes that are mutated are not required for cilia genesis so the cilia look fine under the microscope, however the mutation causes lots of cyst and kidneys enlarge enormously.
Explain PKD in detail
The mutations are such that the structure of the cilia is not affected, the mutations causes enormous number of cysts to develop in the kidney leading to the enlargement of the kidney.
This disease can be autosomal dominant and recessive. The recessive form is associated with the gene PKHD1 whereas the dominant form of the genes are PKD1, PKD2.
What is dominant PKD called
ADPKD (autosomal dominant polycystic kidney disease).
Symptoms of AKPKD
- Hypertension
- Flank Pain
- Hematuria
- Urinary Concentrating Defects
- Nephrolithiasis
- UTIs
- Renal Failure
You can also have cysts in other organs, like in liver and pancreas. You can have hyperlipidemia and aneurysm.
What does PKD1 and 2 code for
Polycystin 1 and 2 respectively. These both are transmembrane proteins.
How does PC1 and PC2 play a role in the function of the celium
If they do not reach the cilium, the cilium doesnt function. This happens in PKD
Explain the mechanism of PKD as explained in lecture. How does Tolvaptin work
In PKD, PC1 and PC2 are effected that are responsible for regulating the concentration of calcium inside the cell. This explains the threshold effect and the two hypothesis concept applied to this disease since both of the genes (PKD1 and PKD2) have to be knocked out in order to cause PKD.
Cysts are formed when the cell continue to proliferate and continue to secrete fluid. In PKD patients, increase in cAMP causes cells to continue to proliferate whereas this doesnt happen in normal individuals. (Refer to the attached image) - Calcium inhibits B Raf which doesnt allow cell proliferation.
cAMP also increase fluid secretion. Vasopressin binds to its receptor, leads to the production of cAMP. cAMP activates CFTR which leads to fluid secretion. Tolvaptin inhibits vasopressin.
