Abstract
Fanconi anemia is a rare disease characterized by congenital malformations, 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, independent of genomic integrity, could correlate with patient phenotype. We evaluated mitochondrial and clinical features of 11 affected individuals 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 possibilities for genotype/phenotype studies based on novel mitochondrial criteria.
| Original language | English |
|---|---|
| Pages (from-to) | 417-426 |
| Number of pages | 10 |
| Journal | Haematologica |
| Volume | 103 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - Feb 28 2018 |
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ASJC Scopus subject areas
- Hematology
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Hypomorphic FANCA mutations correlate with mild mitochondrial and clinical phenotype in Fanconi anemia. / Bottega, Roberta; Nicchia, Elena; Cappelli, Enrico; Ravera, Silvia; De Rocco, Daniela; Faleschini, Michela; Corsolini, Fabio; Pierri, Filomena; Calvillo, Michaela; Russo, Giovanna; Casazza, Gabriella; Ramenghi, Ugo; Farruggia, Piero; Dufour, Carlo; Savoia, Anna.
In: Haematologica, Vol. 103, No. 3, 28.02.2018, p. 417-426.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Hypomorphic FANCA mutations correlate with mild mitochondrial and clinical phenotype in Fanconi anemia
AU - Bottega, Roberta
AU - Nicchia, Elena
AU - Cappelli, Enrico
AU - Ravera, Silvia
AU - De Rocco, Daniela
AU - Faleschini, Michela
AU - Corsolini, Fabio
AU - Pierri, Filomena
AU - Calvillo, Michaela
AU - Russo, Giovanna
AU - Casazza, Gabriella
AU - Ramenghi, Ugo
AU - Farruggia, Piero
AU - Dufour, Carlo
AU - Savoia, Anna
PY - 2018/2/28
Y1 - 2018/2/28
N2 - Fanconi anemia is a rare disease characterized by congenital malformations, 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, independent of genomic integrity, could correlate with patient phenotype. We evaluated mitochondrial and clinical features of 11 affected individuals 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 possibilities for genotype/phenotype studies based on novel mitochondrial criteria.
AB - Fanconi anemia is a rare disease characterized by congenital malformations, 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, independent of genomic integrity, could correlate with patient phenotype. We evaluated mitochondrial and clinical features of 11 affected individuals 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 possibilities for genotype/phenotype studies based on novel mitochondrial criteria.
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UR - http://www.scopus.com/inward/citedby.url?scp=85042793178&partnerID=8YFLogxK
U2 - 10.3324/haematol.2017.176131
DO - 10.3324/haematol.2017.176131
M3 - Article
AN - SCOPUS:85042793178
VL - 103
SP - 417
EP - 426
JO - Haematologica
JF - Haematologica
SN - 0390-6078
IS - 3
ER -