Fanconi anaemia Flashcards
List some clinical phenotype
Microcephaly Mental retardation Developmental delay Skin pigmentation complex Hypoplastic thumbs Aplastic anaemia Predisposition to tumour development Bone marrow failure
Describe the genetics of fanconi anaemia
Autosomal recessive Apart from FANCB which is X-linked 18 identified genes designated FANCA-FANCT (no FANCH or FANCK) FANCA,C,G are the most common FANCD1- mutation in both BRCA2 FANCN- mutation in both PALB2 FANCS- mutation in both BRCA1
What are the cancers that FA patients are suseptable to?
Myelodysplastic syndrome (MDS)
Acute myeloid leukaemia (AML)
Adult patients that have received bone marrow transplants are predisposed to head/neck, gynaecological and/gastrointestinal tumours
FANCD1, FANCN, FANCS complementation groups are suseptable to breast/ovarian cancers
FANCD1 also AML, T cell acute lymphocytic leukaemia (T-ALL), Wilms’ tumour, medulloblastoma and GBM
What is the significance of the FANC genes in normal physiology?
Involved in the interstrand cross link (ICL) repair pathway
FA core complex may travel with the replication machinary
FANCI & FANCD2 recruited to the ICL and is ubiquitinated by FANCL (and the FA core complex) to create a docking site for FANCP, FANCQ (+SLX1) the 5’ nuclease and FANT, (+SNM1A) the 3’ nuclease
They cut around the ICL to “unhook’ it from one strand
Then a ‘bypass’ polymerase replicates around the remains of the ICL to create a suitable structure for a holiday junction and HR
How does FA result in genome stability?
ICLs means that the DNA cannot be completely replicated
Hemi-catenated DNA cannot be separated during anaphase creating an anaphase bridge
After division the DNA breaks off, often at common fragile points (CFPs) from the rest and forms either nuclear bridging or micro nuclei, these can accumulate into a mitotic catastrophe
Increased chromosome breakage with an impaired HR pathway means that the cell attempts to repair it with NHEJ resulting in radial chromosomes which contribute to mitiotic catastrophe
What is the endogenous legion repaired by FA proteins?
Reactive intermediates- aldehydes, can produce ICL and DNA-protein crosslinks
Acetaldehyde is a byproduct of alcohol metabolism and an intermediate of carbohydrate metabolism
Formaldehyde is a byproduct of DNA and histone demethylation, the biosynthesis of purines and certain AAs and found in tabacco smoke, e-cigarettes, aspartame and methanol
Alcohol dehydrogenase- ALD5
Aldehyde dehydrogenase- ALDH2
