Page 65 - Haematologica3

Hypormorphic Fanconi anemia mutations
moderate and severe, respectively, and percentages [0.36 vs. 0.43 (mild), 0.55 vs. 0.37 (moderate), and 0.09 vs. 0.20 (severe)] are not significantly different from those of the entire Italian cohort, although only in one case were the congenital malformations severe. For the hematologic fea- tures, 3 (0.30), 6 (0.50) and 2 (0.20) of patients received mild, moderate and severe scores, respectively, compared with 16% (mild), 27% (moderate), and 49% (severe) of the FA Italian population, suggesting that the missense mutations at residues His913 and Arg951 are associated with better hematologic prognosis.8
Two patients had severe hematologic score and under- went HSCT (together with another 6 affected individuals). However, HSCT per se should not be regarded as a marker of hematologic severity. Indeed, despite their moderate hematologic condition, 2 patients took advantage of hav- ing a suitable healthy matched sibling donor, which is known to provide the best outcome.31 Another 4 under- went familiar or matched unrelated donor HSCT even more than ten years after the first abnormal blood count, when cytopenia dropped from mild/moderate to severe. They are alive and well at 3-7 years after HSCT, except for F9 and F8 who died for cytomegalovirus infection after HSCT and relapse after two HSCT, respectively. Three probands (F2, F6, and F7) with mild hematologic score did not undergo HSCT and their hematologic condition appears to be stable even 11 years (F7) after diagnosis.
Taken together, these data suggest that FA individuals carrying the p.His913Pro and p.Arg951Gln/Trp mutations at one or both the FANCA alleles have a relatively mild phenotype. This conclusion is consistent with data of Faivre et al.,9 showing that patients with altered FANCA protein have milder phenotypes than those with a com- plete loss of FANCA. However, the clinical phenotype depends on many factors, including different genetic and environmental factors, preventing us from confirming any clear correlations. Although FA affected individuals carry- ing the same disease-causing mutation (even among sib- lings) could have different outcomes, the 3 patients homozygous for p.His913Pro have mild/moderate clinical phenotype. Of note, our cohort numbers were limited, as the number of cases studied is relatively low. In order to
assign statistical significance to the correlation, we should explore whether other FA mutations are hypomorphic for the mitochondrial activity and eventually correlate this with mild clinical outcome.
Finally, another factor that could modulate the clinical phenotype in FA is the occurrence of hematopoietic mosaicism, in which cells have lost mitomycin C sensitiv- ity due to back mutations or other genetic mechanisms, as it occurs in almost 20% of cases.32 In consideration of this, F2 and F11 are 2 individuals with potential hematopoietic mosaicism, since one of the two FA mutations was revert- ed to wild-type allele in their LFB cell lines.13 However, none of them were further investigated, preventing us from ascertaining whether and to what extent the mosaicism was present in the bone marrow and blood cells.
In conclusion, at least for the mitochondrial activity, p.His913Pro and p.Arg951Gln/Trp are hypomorphic mutations, which are associated with a mild/moderate phenotype characterized by late onset of the disease and slow hematologic progression. Since the hematopoietic stem cells are relatively sensitive to their redox status,33 a residual activity of mitochondria in cells expressing these, and maybe other missense mutations, could help patients avoid experiencing worsening cytopenia and postponing their eligibility for HSCT. Therefore, we should explore whether other FA mutations with hypomorphic effect could explain the clinical variability in FA.
Funding
This study was supported by Telethon Foundation (grant GGP11076), Cariplo Foundation (2012-0529), Italian Ministry of Health (RF-2010-2309222), AIRFA (Italian Association for Research in Fanconi Anemia), ERG S.p.A., Cambiaso Risso Group, Rimorchiatori Riuniti S.p.A., and Saar Depositi Oleari Portuali S.p.A. We are grateful to the “Cell Line and DNA Biobank from Patients affected by Genetic Diseases” (“G. Gaslini” Institute) and Telethon Genetic Biobank Network (project n. GTB07001) for the sample providing. MF is support- ed by a fellowship (ID 19432) from AIRC (Italian Association of Cancer Research) and RB from "Umberto Veronesi" Foundation.
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