Ciliopathies

Question 1

What are the 2 types of cilia

Answer 1

Motile cilia and non motile cilia which is also called primary cilia

Question 2

How can you differentiate between the 2 cilia

Answer 2

Motile cilia are found in bundles in one cell whereas primary cilia is found sungularly in one cell

Question 3

Where are motile cilia found

Answer 3

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

Question 4

What is the funciton of the primary cilia

Answer 4

They act like an antena and are responsible for receiving signals

Question 5

Where does a cilium arise from? What is the organelle called

Answer 5

Mother centriole

Question 6

Are primary cilia non motile structure

Answer 6

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

Question 7

Is there a structural difference between primary and motile cilia

Answer 7

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

Question 8

What other features are in motile cilia that allow for efficient and effective movement

Answer 8

There are outer dyenin arms, innder dyenin arms and central micotubule pair (accounting for the +2 microtubule fashion). Refer to the attached image.

Question 9

How many primary cilia are there in each cell

Answer 9

Only ONE

Question 10

How does the primary cilia form

Answer 10

It forms from the basal body which is in turn formed from the modified mother centriole

Question 11

Explain the structure of a primary cilium

Answer 11

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.

Question 12

What is needed by the anterograde and retrograde transport in the cilium

Answer 12

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.

Question 13

What are the name of the proteins associated with ciliary gate

Answer 13

Nephrocystins module proteins also called the NPHP and the MKS proteins

Question 14

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?

Answer 14

The protein involved is called the BBSome. It transports stuff from the Golgi body to the ciliary gate.

Question 15

What happens when the IFT proteins are defective

Answer 15

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

Question 16

When does a cilium sprout

Answer 16

Only in the G1 or G0 phase

Question 17

When does the cilium have to disassemble

Answer 17

Before the cell enters mitosis

Question 18

What kind of signals can cilia process, there are 5.

Answer 18

1. Flow/movement
2. Morphogenesis
3. Light
4. Chemical signals
5. Growth factors

Question 19

Generally what kind of disease can we expect when the cilia are defective in a person

Answer 19

Cilia are ubiquituous so we can expect a range of diseases

Question 20

Name the motile ciliopathy

Answer 20

Primary Ciliary Dyskinesia

It is a motile cilipoathy, it doesnt have anything to do with primary cilia

Question 21

What organs will be affected by PCD

Answer 21

Lungs, heart and sperm

Question 22

What are the symptoms of PCD

Answer 22

1. Hydrocephalus (brain cant push the spinal fluid as the cilia doesnt beat as effectively)
2. Respiratory abnormalities
3. Infertility
4. Laterality defects like situs inversus
5. Congential Heart Defects

Question 23

Why does primary or non motile ciliopathies have a range of broad symptoms as compared to PCD

Answer 23

Primary cilia are ubiquitous

Question 24

What are the 2 diseases we should know that are associated with primary ciliopathies

Answer 24

Polycystic Kidney Disease and Von Hippel Lindau Syndrome

Question 25

What is the inheritance pattern for PKD and VHL

Answer 25

Autosomal recessive

Question 26

Explain the symptoms of Meckel Syndrome

Answer 26

It consists of encephalocele, polydactyly and renal cysts

Question 27

What happens in Ciliary Chondrodysplasia

Answer 27

You have abnormal development of the skeletal system so the ribs are narrow and we see shortened fingers and toes.

Question 28

What is the most common form of chondrodysplasia

Answer 28

Jeune Syndrome

Question 29

Are cilia associated with obesity? What are these diseases called?

Answer 29

These diseases are called Bardet-Biedl Syndrome and Alstorm Syndrome. These individuals cilia in the brain are effected so they experience excessive hunger

Question 30

What syndrome is known for its molar tooth sign

Answer 30

Joubert Syndrome

Question 31

What is a common symptoms of most of the ciliopathies

Answer 31

Renal Cyst

Question 32

Explain and contrast the 2 diseases called the nephronophthisis and polycystic kidney disease

Answer 32

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.

Question 33

Explain PKD in detail

Answer 33

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.

Question 34

What is dominant PKD called

Answer 34

ADPKD (autosomal dominant polycystic kidney disease).

Question 35

Symptoms of AKPKD

Answer 35

1. Hypertension
2. Flank Pain
3. Hematuria
4. Urinary Concentrating Defects
5. Nephrolithiasis
6. UTIs
7. Renal Failure

You can also have cysts in other organs, like in liver and pancreas. You can have hyperlipidemia and aneurysm.

Question 36

What does PKD1 and 2 code for

Answer 36

Polycystin 1 and 2 respectively. These both are transmembrane proteins.

Question 37

How does PC1 and PC2 play a role in the function of the celium

Answer 37

If they do not reach the cilium, the cilium doesnt function. This happens in PKD

Question 38

Explain the mechanism of PKD as explained in lecture. How does Tolvaptin work

Answer 38

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.