5. AD - haploinsufficiency

Question 1

What is meant by the term ‘haploinsufficiency’?

Answer 1

Both alleles of a gene required for normal function. Inactivation of one allele produces a clinical phenotype.

Gene is haploinsufficient if all mutation types produce same phenotype due to LoG and AD inheritance is observed

Question 2

What three types of genes display haploinsufficiency?

Answer 2

1. Highly expressed genes - large amount of product needed
2. Dosage sensitive genes - involved in quantitative signalling pathway, gene products that cooperate in interactions with fixed stochiometry
3. Imprinted genes - only one allele expressed, mutation therefore dominant. Often associated with systemic, wide spectrum roles

Question 3

Give three examples of single gene disorders associated with haploinsufficiency

Answer 3

1. HCM - genes involved in structure/function of sarcomere of heart (e.g. MYH7, MYBPC3)
2. Alagille syndrome - heart, liver, eye, skeletal defects. JAG1 involved in transcriptional activation of factors for cell differentiation
3. HNPP - repeated focal pressure palsies, PMP22 deletion, essential part of peripheral nerve myelin sheath

Question 4

Give two examples of haploinsufficiency in contiguous gene deletion syndromes

Answer 4

1. DiGeorge syndrome (22q11.2 deletion) - haploinsufficiency of TBX1. TF vital for developmental regulation
2. Cri-du-chat syndrome (5p15 deletions) - certain deletions for particular features

Question 5

Give three examples of haploinsufficiency in cancer

Answer 5

1. p53 - mutated in >50% of tumours, germline associated with Li Fraumeni
2. PTEN - mutated in range of tumours, germline associated with Cowden syndrome. PTEN negatively regulates cellular proliferation
3. BRCA1 - breast and ovarian cancer, conforms to 2 hit model. Second somatic hit inactivates functional copy of the gene