Genetic mechanisms of congenital neutropenia

Question 1

What cell counts is severe and very severe nuetropenia?

Answer 1

<0.5 x 109/l

<0.2 x 109/l

Question 2

what are 3 reasons for neutropenia (orignin of defect in BM?)

Answer 2

ineffective granulopoiesis
defective release
destruction at source (e.g. autoimmunity)

Question 3

What could shorten intravascular lifespan?

Answer 3

immune-mediated destruction

Question 4

What happens in neonatal alloimmune neutropenia that resolves itself?

Answer 4

Maternal antibodies against paternal antigen on neutrophils leads to neutropenia.

Question 5

What is happening in autoimmune neutropenia? What is severity, and does it resolve?

Answer 5

anti-neutrophil antibodies.

relatively minor defects and spontaneous remission.

Question 6

What myeloid maturation stage does SCN stop at?

Answer 6

development arrests at the promyelocyte stage.

Question 7

What kind of inheritance does SCN have?

Answer 7

sporadic (somatic), AD, AR and X linked.

Question 8

What gene and protein does SCN1 affect?

Answer 8

Neutrophil elastase deficiency and ELANE is the gene.

Question 9

What are the mutations causign SCN that affect Turksih and israelian ethnicities?

Answer 9

Turkish is HAX1 Ichanges mitcohondrial membrane polarity) and Israel is G6PC3 (changes protein glycosylation patterns)

Question 10

What is SCN2 protein and gene?

Answer 10

GFI1 deficiency and GFI1 gene.

Question 11

What can be performed to show arrest maturation at the promyelocyte stage?

Answer 11

bone marrow aspirate.

Question 12

What SCN is most prevalent and what are people more susceptible to?

Answer 12

Acute myeloid leukaemia and MDS.

Question 13

What do mutations G6PC3, JAGN1, VPS13B and ELANE all affect?

Answer 13

Cause misfolding accumulation in the ER whihc is thought to trigger UPR and apoptosis,

Question 14

Which mutations cause cahnges in protein glycosylation pattern?

Answer 14

G6PC3, VPS13B and JAGN1.

Question 15

What does defect in VPS45 cause?

Answer 15

defects in membrane trafficknig in ER and increase apoptosis independently of ER.

Question 16

What are the features of JAGN1?

Answer 16

altered N glycosylation and increased apopotosis.

Paucity of granules within neutrophils.

Question 17

What oher way might JAGN1 (overexpressed) cause cell death?

Answer 17

Tirggering calcium dependent cell death program

Question 18

What are two TFs important for granulcoyte formation?

Answer 18

C/EBPe and PUI( encoded by SPI1).

Question 19

What regulates the expression of C/EBP1 and SPI1 (encodes PUI)?

Answer 19

GFI1 TF regulates their expression.

Deficiency causes myeloid maturatoin arrest.

Question 20

What autosomal dominant mutation can cause severe congenital neutropenia and cyclic neutropnia?

Answer 20

autosomal dominant ELANE mutations.

Question 21

How is GC-SF supposed to help SCD?

Answer 21

disrupts apoptosis by activating Akt/BCl2 that activates an emergency C/EBP beta dependentgranulopoiesis.
And can rescue neutrophils from apoptosis.

Question 22

What two cancers are SCN assocaied with? What might exacerbate this?

Answer 22

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.

Question 23

What is he G185R mutation in ELANE associated with?

Answer 23

With very server neutropenia and high risk of leukaemic transformations.

Question 24

What do mutatoins spotted in GCSF R of people with SCN do to the protein?

Answer 24

Creates a truncated protein that has negative regulator removed.
However unsure whether this is causing leukaemia or is a bystander.

Question 25

what are cytogenetic studies looking for?

Answer 25

AML and MDS.

Question 26

Which very rare form of SCN is mostly caused by a compound heterozygous mutations in SBDS?

Answer 26

Schwachman-diamond syndrome.

Question 27

As well as SCD, what othe immunological feature and sbnormalities are schwachman diamond syndrome associated with?

Answer 27

pancytopenai (no RBC, WBC or platlets)
pancratic exocrine dfeciceny
skeletal abonormalities and eczema.

Question 28

What is the SBDS proteins? how might it be treated?

Answer 28

ribosomal maturation factor.

prophylaxis and enzyme replcement.

Question 29

Which mutations causing SCD is associateed with hhypoagammaglobulinaemia and warts and infections?

Answer 29

WHIM syndroe with autosomal dominant mtation in CXCR4.

Question 30

What treamtent options are there for WHIM syndrome?

Answer 30

GCSF/ GMCSF and plerixafor (CXCR4 antagonist)