Genetic mediators of development: The molecular toolbox

Question 1

What types of products do genes required for normal development encode?

Answer 1

Signaling molecules, receptors, DNA transcription factors, components of the extracellular matrix, enzymes, transport systems, and other proteins.

Question 2

What is the Sonic hedgehog (Shh)-Patched (Ptch)-Gli pathway involved in?

Answer 2

It is involved in signaling pathways that regulate various developmental processes.

Question 3

What disorders are associated with perturbations in the Shh signaling pathway?

Answer 3

• Holoprosencephaly
• Smith–Lemli–Opitz syndrome
• Gorlin syndrome
• Greig cephalopolysyndactyly syndrome
• Rubenstein–Taybi syndrome

Question 4

What are paracrine signaling molecules?

Answer 4

Proteins that diffuse across small distances to induce a response in neighboring cells.

Question 5

Name the four major families of paracrine signaling molecules.

Answer 5

• Fibroblast Growth Factor (FGF) family
• Hedgehog family
• Wingless (Wnt) family
• Transforming Growth Factor β (TGF-β) family

Question 6

What is the primary receptor for Sonic hedgehog (Shh)?

Answer 6

Patched (Ptch)

Question 7

What is the primary consequence of mutations in the PATCHED (PTC) gene?

Answer 7

Gorlin syndrome, characterized by rib anomalies, cysts of the jaw, and basal cell carcinomas.

Question 8

What are the main features of Fibroblast Growth Factor Receptors (FGFRs)?

Answer 8

Highly homologous glycoproteins with a signal peptide, three Ig-like domains, a membrane-spanning segment, and an intracellular tyrosine kinase domain.

Question 9

What is achondroplasia (ACH) characterized by?

Answer 9

Disproportionate short stature and macrocephaly.

Question 10

What mutation is commonly associated with achondroplasia?

Answer 10

A glycine → arginine substitution in FGFR3.

Question 11

What is thanatophoric dysplasia?

Answer 11

A lethal short-stature syndrome caused by markedly increased activation of FGFR3.

Question 12

What are craniosynostosis syndromes?

Answer 12

Disorders characterized by premature fusion of cranial sutures, misshapen skulls, and limb defects.

Question 13

Which FGFR mutations are associated with craniosynostosis syndromes?

Answer 13

• FGFR1
• FGFR2
• FGFR3

Question 14

What is the role of the Wnt family of genes?

Answer 14

They are involved in establishing polarity during limb formation and regulating various developmental processes.

Question 15

What genetic conditions are caused by pathogenic variants in WNT genes?

Answer 15

• Tetra-amelia
• Robinow syndrome
• Deficiency of the ulna and fibula
• Odontoonychodermal dysplasia

Question 16

What does the TGF-β supergene family include?

Answer 16

• TGF-β family
• Bone morphogenetic protein (BMP) family
• Activin family
• Vg1 family

Question 17

What skeletal abnormalities are caused by mutations in cartilage-derived morphogenetic protein 1 (CDMP1)?

Answer 17

Brachydactyly and acromesomelic dysplasia.

Question 18

What is the RTK-MAPK signaling pathway responsible for?

Answer 18

Regulating gene expression, cell division, differentiation, and death.

Question 19

What syndrome is characterized by short stature, facial features, neck webbing, and congenital heart disease?

Answer 19

Noonan syndrome.

Question 20

What is the effect of mutations in the Noggin gene?

Answer 20

Causes fusion of bones in various joints.

Question 21

What is the role of Noggin in human joints?

Answer 21

Inhibits the function of BMPs, causing fusion of bones in joints due to excessive cartilage formation.

Mutations in the Noggin gene lead to synostosis, affecting the spine, middle ear bones, and limbs.

Question 22

What are the four major families of paracrine signaling molecules?

Answer 22

• Fibroblast growth factor (FGF) family
• Hedgehog family
• Wingless (Wnt) family
• Transforming Growth Factor β (TGF-β) family

These molecules bind to receptors to effect responses in neighboring cells.

Question 23

What are transcription factors?

Answer 23

Proteins that activate or repress the transcription of other genes.

They often regulate multiple genes and have pleiotropic effects when mutated.

Question 24

Name three families of transcription factors mentioned.

Answer 24

• HOX family
• SOX family
• T-box family

These families share specific properties and play pivotal roles in development.

Question 25

What is the prototypic SOX gene?

Answer 25

SRY (sex-determining region of the Y chromosome) gene. ## Footnote It encodes the mammalian testis-determining factor.

Question 26

What disorder is caused by mutations in SOX9?

Answer 26

Campomelic dysplasia and sex reversal producing XY females. ## Footnote SOX9 is involved in chondrogenesis and regulates Col2A1 expression.

Question 27

What are extracellular matrix proteins (EMPs)?

Answer 27

Secreted macromolecules that provide scaffolding for tissues and organs. ## Footnote Examples include collagens, fibrillins, and proteoglycans.

Question 28

What is the function of integrins?

Answer 28

Integrate the extracellular matrix and the cytoskeleton, facilitating cell adhesion. ## Footnote They play a role in cell migration and attachment to the extracellular matrix.

Question 29

What condition is caused by mutations in LAMC2?

Answer 29

Autosomal recessive junctional epidermolysis bullosa (JEB). ## Footnote This condition leads to spontaneous blistering of the skin due to improper anchoring of epithelial cells.

Question 30

What is Hirschsprung disease (HSCR)?

Answer 30

A disorder characterized by hypomotility of the bowel due to reduced or absent nerve cells in the enteric tract. ## Footnote It occurs in approximately 1 in 5000 live births and has a higher incidence in males.

Question 31

What gene is most commonly mutated in nonsyndromic Hirschsprung disease?

Answer 31

RET (re arranged during transfection) gene. ## Footnote Mutations in RET lead to inactivation, affecting neural crest migration and differentiation.

Question 32

What is Waardenburg–Shah syndrome?

Answer 32

A disorder associated with mutations in EDNRB or EDN3, leading to HSCR and melanocyte abnormalities. ## Footnote It includes symptoms such as hypopigmented skin patches and sensorineural hearing loss.

Question 33

What is the primary function of glial cell line derived neurotrophic factor (GDNF)?

Answer 33

Acts as a ligand for the RET receptor, facilitating neural crest migration into the bowel. ## Footnote Proper signaling through RET is essential for the development of enteric nerve cells.

Question 34

True or False: Mutations in SOX10 are only associated with Waardenburg–Shah syndrome.

Answer 34

False. ## Footnote Mutations in SOX10 can lead to other conditions, including defects in neural crest cell development.

Question 35

Fill in the blank: Mutations in _______ cause Marfan syndrome.

Answer 35

fibrillin-1 ## Footnote Marfan syndrome is characterized by cardiovascular issues and skeletal abnormalities.

Question 36

What is a common feature of disorders caused by mutations in transcription factors?

Answer 36

Pleiotropic effects. ## Footnote These disorders often affect multiple systems due to the broad regulatory roles of transcription factors.

Question 37

What is the role of extracellular matrix proteins during development?

Answer 37

Act as active mediators by facilitating cell migration and separating groups of cells. ## Footnote They provide structural support and influence cellular behavior.