Dominant Mutations

Question 1

What are the reasons a mutant phenotype is dominant?

Answer 1

Mutation leads to Constitutive expression/over-expression of protein
= Gain of function / deregulation (if regulatory protein).

(New activity, misregulated or enhanced activity)

Mutant protein is toxic

Mutant protein inhibits WT protein encoded on WT allele
= Dominant-negative effect/Antimorphic.

(Loss of function in haploinsufficiency)

Question 2

Example of constitutive activation dominant phenotype?

Answer 2

Achondroplasia = FGFR3 missense mutation.

FGFR3 is RTK which is inactive as monomer.
Binding ligand causes dimerisation and transphosphorylation leading to receptor activation.
= activating MAP-kinase pathway.

FGFR3 is negative control of bone growth = in young adults, its ligand induces growth arrest.

This mutation makes receptor constitutively active = inducing dwarfism.
IN Heterozygotes = dominant!

Question 3

What is example of dominant-negative effect?

Answer 3

Osteogenesis Imperfecta:

Mutant protein inhibits WT protein on WT allele
= mutant protein loses its own activity and inhibits activity of WT.

Type 1 collagen contains 3 chains in its triple helix.
2 Col1A1 and 1 Col1A2.
(2n Col1A1 and 1n Col1A2).

Mutant Col1A1 can assemble with WT Col1A2 but in the wrong way…
n normal chains, n mutant chains of Col1A1 can associate with n chains of Col1A2.
= will form malformed triple helices.

3/4 of triple helices will be abnormal and mutant product antagonises WT product by sequestering in inactive, abnormal triple helices.

Question 4

What does dominant-negative really mean?

Answer 4

In heterozygotes, function of mutant protein is lost.
AND
Effect on phenotype is dominant as mutant product gains new function = disrupting normal function of WT product.

= EXPECT in proteins with di or polymeric forms….

Question 5

Why must be careful when assigning dominance/recessivity to alleles?

Answer 5

We need to assign dominance recessivity to PHENOTYPES rather than alleles.

In the case of Sickle cell anaemia:
Phenotype can be anemic but resistant to malaria….
or healthy and sensitive.

Indeed, sickle cell anemia is recessive in normal conditions for heterozygotes…
But in low oxygen atmosphere, anemia phenotype is dominant.

So need to refer to phenotype, not allele, and explain depending on the conditions!