Genetic mechanisms of congenital neutropenia Flashcards
What cell counts is severe and very severe nuetropenia?
<0.5 x 109/l
<0.2 x 109/l
what are 3 reasons for neutropenia (orignin of defect in BM?)
ineffective granulopoiesis
defective release
destruction at source (e.g. autoimmunity)
What could shorten intravascular lifespan?
immune-mediated destruction
What happens in neonatal alloimmune neutropenia that resolves itself?
Maternal antibodies against paternal antigen on neutrophils leads to neutropenia.
What is happening in autoimmune neutropenia? What is severity, and does it resolve?
anti-neutrophil antibodies.
relatively minor defects and spontaneous remission.
What myeloid maturation stage does SCN stop at?
development arrests at the promyelocyte stage.
What kind of inheritance does SCN have?
sporadic (somatic), AD, AR and X linked.
What gene and protein does SCN1 affect?
Neutrophil elastase deficiency and ELANE is the gene.
What are the mutations causign SCN that affect Turksih and israelian ethnicities?
Turkish is HAX1 Ichanges mitcohondrial membrane polarity) and Israel is G6PC3 (changes protein glycosylation patterns)
What is SCN2 protein and gene?
GFI1 deficiency and GFI1 gene.
What can be performed to show arrest maturation at the promyelocyte stage?
bone marrow aspirate.
What SCN is most prevalent and what are people more susceptible to?
Acute myeloid leukaemia and MDS.
What do mutations G6PC3, JAGN1, VPS13B and ELANE all affect?
Cause misfolding accumulation in the ER whihc is thought to trigger UPR and apoptosis,
Which mutations cause cahnges in protein glycosylation pattern?
G6PC3, VPS13B and JAGN1.
What does defect in VPS45 cause?
defects in membrane trafficknig in ER and increase apoptosis independently of ER.
What are the features of JAGN1?
altered N glycosylation and increased apopotosis.
Paucity of granules within neutrophils.
What oher way might JAGN1 (overexpressed) cause cell death?
Tirggering calcium dependent cell death program
What are two TFs important for granulcoyte formation?
C/EBPe and PUI( encoded by SPI1).
What regulates the expression of C/EBP1 and SPI1 (encodes PUI)?
GFI1 TF regulates their expression.
Deficiency causes myeloid maturatoin arrest.
What autosomal dominant mutation can cause severe congenital neutropenia and cyclic neutropnia?
autosomal dominant ELANE mutations.
How is GC-SF supposed to help SCD?
disrupts apoptosis by activating Akt/BCl2 that activates an emergency C/EBP beta dependentgranulopoiesis.
And can rescue neutrophils from apoptosis.
What two cancers are SCN assocaied with? What might exacerbate this?
acute myeoid leukemia and myelodysplasis MDS).
May be exacerabated by GCSF treatment– however it may allow them to survive long enough for full phenotype to arise.
What is he G185R mutation in ELANE associated with?
With very server neutropenia and high risk of leukaemic transformations.
What do mutatoins spotted in GCSF R of people with SCN do to the protein?
Creates a truncated protein that has negative regulator removed.
However unsure whether this is causing leukaemia or is a bystander.
