L17-DSB repair deficiency disorders

Question 1

state the 2 clinical phenotypes seen in NHEJ deficient patients?

Answer 1

• microcephaly

- immunodeficient/RS

Question 2

how do NHEJ mutations cause immunodeficiency issues?

Answer 2

when VDJ recombination occurs, DNA DSBs are physiologically made to form the different types of ABs
VDJC regions are cut by RAG1/2 which induced DSBs
but the is fixed by mismatch repair causing oncogenic chomosomal translocations such as IgH/Cmyc

Question 3

why do NHEJ mutations cause microcephaly?

Answer 3

normally, neuroprogenitor cells expand rapidly to produce enough cells to allow the brain to develop properly, symmetric division = increases SC pool whereas asymmetric division = allows differentiation into different neuronal cell types to occur
genetic mutations cause cell cycle to slow down and reduce the number of stem cells in the pool= neuroprogenitor cell pool reduces causing brain to slow down in development=small brain/head
-rapid dividing neuroporgenitor cells cause an increase in DSBs
- usually cells remain in the VZ region, but experiments showed there to be more apoptosis cells (due to p53 dependent apoptosis) in the SVZ region = where they begin to differentiate and come out of cycle

Question 4

state the 2 clinical phenotypes seen in HR deficient patents?

Answer 4

• immunodeficiency

- microcephaly

Question 5

how do HR mutations cause immunodeficiency?

Answer 5

- loss of ATM doesn't result in VDJ recombination issues, but causes class switching issues
No ATM = alt-ej is switched on = causes non productive IgH loci switching = produces a non functional IgG transcript

Question 6

why do HR mutations cause microcephaly?

Answer 6

as rapidly dividing neuro-progenitor cells generate more ABs, they rely on HR repair
instead apoptosis of these neuroprogeintor cells is p53-dependent and not ATM dependent (like in NHEJ)Q