Signalling & Genetics of Craniofacial Disorders

Question 1

Bone morphogenic proteins (BMP) when applied to bone defects would:

Answer 1

• promote osteoblast differentiation

- accelerate bone healing

Question 2

Which bone morphogenic proteins (BMP) are FDA approved?

Answer 2

BMP-2 and BMP-7

Question 3

BMP is a subfamily of which superfamily?

Answer 3

Transforming growth factor (TGF)-beta

Question 4

TGF-beta superfamily has which subfamilies?

Answer 4

TGF-beta, activin, and BMP

Question 5

What is similar between subfamilies of (TGF)-beta?

Answer 5

Structurally similar and therefore signal transduction pathway is similar

Question 6

Growth factors like BMP are found where?

Answer 6

In small portion by weight («10%) in bone

Question 7

Signal transduction requires:

Answer 7

• protein-protein interaction (direct binding)
• post translational modification (like phosphorylation, etc)
• usually needs growth factor-receptor-signal transducer-transcription factor (ie. there are 4 important players in signal transduction)

Question 8

Where do growth factors bind?

Answer 8

membrane bound proteins (bind with very high affinity)

Question 9

Binding of growth factors leads to:

Answer 9

cascade of intracellular secondary messages, and then modulation of other proteins or enhanced transcription of specific genes

Question 10

growth factor receptors consist of which peptide domains?

Answer 10

extracellular, transmembrane and intracellular

Question 11

2 types of kinase receptors

Answer 11

tyrosine kinase receptor and serene/threonine kinase receptor (because these amino acids can be phosphorylated)

Question 12

Activation of TGF-beta/BMP signalling

Answer 12

• two types of receptors (I and II)
• growth factor dimerize and bind to type II causes conformational change
• type I receptor recruited and forms complex with type II-growth factor
• SMAD complex recruited to activated receptor complex, phosphorylation occurs
• SMAD then acts as transcription factor

Question 13

What is SMAD?

Answer 13

A signal transducer

Question 14

What is a signal transducer?

Answer 14

molecules/proteins that are utilized for intracellular signalling (membrane to nucleus)

Question 15

5 examples of signal transducers and what type of signalling they’re involved in

Answer 15

Smad in TGF/BMP signalling
MAPK in MAP kinase signalling
JAK/STAT is JAK/STAT signalling
IKK in NF-kB signalling
GSK and beta-catenin in Wnt signalling

**probably more information than needed

Question 16

growth factors activity controlled at multiple steps by

Answer 16

• inhibition by pro domain
• inhibition by ECM binding protein
• inhibition by ECM antagonists
• stored within ECM

Question 17

Growth factor examples in TGF-beta signalling

Answer 17

• pro-peptide (which makes small latent complex/SLC with mature TGF-beta)
• latent TGF-beta binding protein (LTBP) which makes large latent complex with SLC
• fibrillin, collagen, (ECM) important for growth factor activity control

Question 18

TGF-beta controls

Answer 18

proliferation, differentiation, and other functions in many cell types

Question 19

TGF-beta two main abilities

Answer 19

• induces cell transformation

- acts as negative autocrine growth factor

Question 20

Disregulation of TGF beta causes

Answer 20

Marfan syndrome, camurati-engelmann disease and cancer, fibrosis, scleroderma etc

Question 21

small latent complex (SLC)

Answer 21

TGF beta propeptide bound to TGF beta, and dimerized. Inactive.

Question 22

Marfan syndrome

Answer 22

• autosomal dominant
• malocclusion, micrognathia, severe periodontal disease, narrow face, tooth crowding
• mutant fibrillin releases TGF-beta (improper activation of growth factor)

Question 23

Loeys-Dietz syndrome (LDS)

Answer 23

• overlapping symptoms with MFS except:
  - low set ears, eyes far apart (hypertelorism)
  - bifid uvula, cleft palate
• TGF-beta receptors 1 or 2 mutation

Question 24

Fibrodysplasia ossificans progressiva (FOP)

Answer 24

-BMP receptor (ACVRI/ALK2) mutation

Question 25

How can mutations in different genes cause the same abnormal phenotypes?

Answer 25

if gene mutations disrupt the same pathways (like in marfan syndrome and LDS), same phenotype could be observed