7. AD - dominant negative effect

Question 1

What is meant by the term ‘dominant-negative’

Answer 1

Variants that impair the function of the variant allele but also reduce the function of the protein encoded by the normal allele

More severe effect than LoF variant in the same gene

E.g. Protein-protein interactions in multi subunit protein complex

Question 2

Give an example of a disease/gene where NMD plays a role in a dominant-negative mechanism of disease

Answer 2

SOX10 (Waardenburg syndrome)

Nonsense variants that escape NMD - dominant-negative activity - severe phenotype

Nonsense variants that lead to NMD - no dominant-negative effect - milder phenotype

Question 3

Describe how AD variants in GJB2 cause disease

Answer 3

Small number of AD variants

6 connexin proteins oligomerise to form hemichannel unit - slign with those in neighbouring cells to form K+ channels

Dominant negative GJB2 variants form structurally abnormal Cx26 molecules - impaired K+ permeability

Question 4

Describe the mechanism of disease in the different types of osteogenesis imperfecta

Answer 4

COL1A1 and COL1A2 encode type 1 procollagen chains - 3 chains wind into ttriple helixes to form mature collagen (major structural protein)

Type 1: Haploinsufficiency - LoF in Col1A1 –> decrease in amount of procollagen due to NMS - mild disease

Type 2, 3, 4: Dominant-negative due to glycine substitution in triple helical region –> abnormal procollagen which disrupts triple helix formation - severe disease

Question 5

Other than GJB2-related deafness and OI, give. an example of dominant-negative inheritance in rare diseases

Answer 5

Marfan syndrome (FBN1) - connective tissue disorder, aortic aneurysm and dissection

Dom-neg variants cause ectopia lentis

LoF variants cause decrease in aortic wall strength, increased risk of cardiac death compared to dom-neg

Question 6

Give an example of dominant-negative inheritance in cancer

Answer 6

p53 - TF that mediates changes in gene expression - promotes apoptosis and senescence to eliminate damaged cells and suppress tumourogenesis

Germline variants cause Li Fraumeni syndrome

Variants in DNA binding domain are dom-neg and cause reduced transcriptional activity