Mutations in this gene are the most common cause of
Fanconi's anaemia. and it is one of the largest FA genes. Hundreds of different
mutations have been recorded with 30% point mutations, 30% 1-5 base pair microdeletions or microinsertions, and 40% large deletions, removing up to 31
exons from the gene. These large deletions have a high correlation with specific breakpoints and arise as a result of
Alu mediated recombination. A highly relevant observation is that different mutations produce Fanconi anaemia phenotypes of varying severity. Patients
homozygous for null-mutations in this gene have an earlier onset of
anaemia than those with mutations that produce an altered or incorrect protein. However, as most patients are
compound heterozygotes, diagnostic screening for mutations is difficult. Certain founder mutations can also occur in some populations, such as the deletion exon 12-31 mutation, which accounts for 60% of mutations in Afrikaners.
Involvement in FA/BRCA pathway In cells from Fanconi anaemia patients, FA core complex induction of
FANCD2 ubiquitination is not observed, assumably a result from impaired complex formation due to the lack of a working FANCA protein. Ultimately, regardless of specific mutation, it is disruption of this FA/BRCA pathway that results in the adverse cellular and clinical
phenotypes common to all FANCA-impaired Fanconi anaemia sufferers.
coimmunoprecipitation from
in vitro synthesis, and coimmunoprecipitation from cell extracts shows that the site of interaction is between the terminal amino group of FANCA and the central part of BRCA1, located within amino acids 740–1083. However, as FANCA and
BRCA1 undergo a constitutive interaction, this may not depend solely on detection of actual DNA damage. Instead BRCA1 protein may be more crucial in the detection of double stranded DNA breaks, or an intermediate in interstrand
crosslink (ICL) repair, and rather serve to bring some of the many DNA repair proteins it interacts with to the site. One such protein would be FANCA, which in turn may serve as a docking site or anchor point at the site of ICL damage for the FA core complex. Alternatively, BRCA1 might localize FANCA to the site of DNA damage and then release it to initiate complex formation. Studies using clonogenic
myeloid progenitors (CFU-GM) have also shown that the frequency of CFU-GM in normal
bone marrow increased and their proliferative capacity decreased exponentially with age, with a particularly marked proliferative impairment in Fanconi anaemia afflicted children compared to age-matched healthy controls. As haematopoietic progenitor cell function begins at birth and continues throughout life, it is easily inferred that prolonged incapacitation of FANCA protein production results in total haematopoietic failure in patients.
Potential impact on erythroid development The three distinct stages of
mammalian erythroid development are primitive, foetal and adult definitive. Adult, or definitive
erythrocytes are the most common blood cell type and characteristically most similar across mammalian species. Primitive and foetal erythrocytes however, have markedly different characteristics. These include: they are larger in size (primitive even more so than foetal), circulate during early stages of development with a shorter lifespan, and, in particular, primitive cells are
nucleated. As the reasons for these disparities are not well understood, FANCA may be a gene responsible for instigating these morphological differences when considering its variations in erythrocyte expression. In primitive and foetal erythrocyte precursors, FANCA expression is low, and almost zero during
reticulocyte formation. The marginal overall increase in the foetal stage is dwarfed by its sudden increase in expression solely during adult definitive proerythroblast formation. Here, the mean expression increases by 400% compared to foetal and primitive erythrocytes, and covers a huge margin of deviation. As FANCA is heavily implicated in controlling cellular proliferation, and often results in patients developing
megaloblastic anaemia around age 7, a haematological disorder marked physically by proliferation-impaired, oversized erythrocytes, it is possible that the size and proliferative discrepancies between primitive, foetal and adult erythroid lineages may be explained by FANCA expression. As FANCA is also linked to cell-cycling and its progression from G2 phase, the stage impaired in megaloblastic anaemia, its expression in definitive proerythroblast development may be an upstream determinant of erythroid size.
Implications in cancer FANCA mutations have also been implicated in increased risks of
cancer and malignancies. For example, patients with homozygous null-mutations in FANCA have a markedly increased susceptibility to
acute myeloid leukaemia. Furthermore, as FANC mutations in general affect
DNA repair throughout the body and are predisposed to affect dynamic
cell division particularly in
bone marrow, it is unsurprising that patients are more likely to develop
myelodysplastic syndromes (MDS) and
acute myeloid leukaemia. == Mouse knockout ==