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Bone Marrow Failure
Hypomorphic FANCA mutations correlate
with mild mitochondrial and clinical phenotype in Fanconi anemia
Roberta Bottega,1* Elena Nicchia,2* Enrico Cappelli,3 Silvia Ravera,4 Daniela De Rocco,1 Michela Faleschini,1 Fabio Corsolini,5 Filomena Pierri,3 Michaela Calvillo,3 Giovanna Russo,6 Gabriella Casazza,7 Ugo Ramenghi,8 Piero Farruggia,9 Carlo Dufour3 and Anna Savoia1,2
1Institute for Maternal and Child Health – IRCCS “Burlo Garofolo”, Trieste;
2Department of Medical Sciences, University of Trieste; 3Clinical and Experimental Hematology Unit, “G. Gaslini” Children’s Hospital, Genoa; 4Department
of Pharmacy (DIFAR), Biochemistry Lab, University of Genoa; 5U.O.S.D. Centro di Diagnostica Genetica e Biochimica delle Malattie Metaboliche, “G. Gaslini” Children’s Hospital, Genoa; 6Oncology Hematology Pediatric Unit, “Policlinico – Vittorio Emanuele”, University of Catania; 7Pediatric Onco-Hematology, Azienda Ospedaliera/
Universitaria Pisana, Pisa; 8Department of Pediatric and Public Health Sciences, University of Torino and 9Pediatric Onco-Hematology, ARNAS Civico Hospital, Palermo, Italy
Ferrata Storti Foundation
Haematologica 2018 Volume 103(3):417-426
*RB and EN contributed equally to this study.
ABSTRACT
Fanconi anemia is a rare disease characterized by congenital malfor- mations, aplastic anemia, and predisposition to cancer. Despite the consolidated role of the Fanconi anemia proteins in DNA repair, their involvement in mitochondrial function is emerging. The purpose of this work was to assess whether the mitochondrial phenotype, inde- pendent of genomic integrity, could correlate with patient phenotype. We evaluated mitochondrial and clinical features of 11 affected individ- uals homozygous or compound heterozygous for p.His913Pro and p.Arg951Gln/Trp, the two residues of FANCA that are more frequently affected in our cohort of patients. Although p.His913Pro and p.Arg951Gln proteins are stably expressed in cytoplasm, they are unable to migrate in the nucleus, preventing cells from repairing DNA. In these cells, the electron transfer between respiring complex I-III is reduced and the ATP/AMP ratio is impaired with defective ATP production and AMP accumulation. These activities are intermediate between those observed in wild-type and FANCA-/- cells, suggesting that the variants at residues His913 and Arg951 are hypomorphic mutations. Consistent with these findings, the clinical phenotype of most of the patients carrying these mutations is mild. These data further support the recent finding that the Fanconi anemia proteins play a role in mitochondria, and open up pos- sibilities for genotype/phenotype studies based on novel mitochondrial criteria.
Introduction
Fanconi anemia (FA) is a rare autosomal or X-linked recessive disease character- ized by congenital abnormalities, bone marrow failure, and predisposition to cancer (mainly leukemia and squamous cell carcinomas). FA is caused by mutations in at least 22 genes. The FA proteins co-operate in a pathway whose role in maintaining the genome integrity is well known. In the presence of DNA damage, eight of the FA proteins, including FANCA, assemble in a nuclear 'core complex' responsible for monoubiquitination of FANCD2, an FA player that localizes in foci where it inter- acts with other FA components for DNA repair.1 FA cells are consistently hypersen- sitive to interstrand cross-link inducing agents, such as diepoxybutane (DEB) or mit- omycin C (MMC).
In addition to their nuclear localization, the FA proteins are also localized in the cytoplasm, where they are likely to be involved in different processes that have yet to be defined, such as maintenance of mitochondrial aerobic metabolism, suppres-
Correspondence:
anna.savoia@burlo.trieste.it
Received: July 12, 2017.
Accepted: December 14, 2017. Pre-published: December 21, 2017.
doi:10.3324/haematol.2017.176131
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/3/417
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haematologica | 2018; 103(3)
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