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Fanconi's anemia

Fanconi anemia (FA) is a rare genetic disease that affects children and adults from all ethnic backgrounds. Named for the Swiss pediatrician who originally described this disorder, Guido Fanconi, FA is characterized by short stature, skeletal anomalies, increased incidence of solid tumors and leukemias, bone marrow failure (aplastic anemia), and cellular sensitivity to DNA damaging agents such as mitomycin C. more...

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Causes

FA is primarily a autosomal recessive genetic condition. There are at least 8 genes for which mutations in are known to cause FA: A, C, D1, D2, F, G, L, and B. FANCB is the one exception to FA being autosomal recessive, as this gene is on the X chromosome. For an autosomal recessive disorder, both parents must be carriers in order for a child to inherit the condition. If both parents are carriers, there is a 25% risk with each pregnancy for the mother to have an affected child. Approximately 1,000 persons worldwide presently suffer from the disease. The carrier frequency in the Ashkenazi Jewish population is about 1/90. Genetic counseling and genetic testing is recommended for families that may be carriers of Fanconi anemia.

Because of the failure of the components of the blood - white and red blood cells and platelets - the body cannot successfully combat infection, fatigue or spontaneous hemorrhage or bleeding. Bone marrow transplantation is the accepted treatment to repair the hematological problems associated with FA. Patients face an increased risk of acquiring cancer and other serious health problems throughout their lifetime.

Prognosis

Many patients eventually develop acute myelogenous leukemia (AML). Older patients are extremely likely to develop head and neck, esophageal, gastrointestinal, vulvar and anal cancers. Patients who have had a successful bone marrow transplant and, thus, are cured of the blood problem associated with FA still must have regular examinations to watch for signs of cancer. Many patients do not reach adulthood.

The overarching medical challenge that Fanconi patients face is a failure of their bone marrow to produce blood cells. In addition, Fanconi patients normally are born with a variety of birth defects. For instance, 90% of the Jewish children born with Fanconi's have no thumbs. A good number of Fanconi patients have kidney problems, trouble with their eyes, developmental retardation and other serious defects.

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Mitochondrial alterations in fanconi anemia fibroblasts following ultraviolet A or psoralen photoactivation
From Photochemistry and Photobiology, 2/1/02 by Rousset, Solange

Mitochondrial Alterations in Fanconi Anemia Fibroblasts Following Ultraviolet A or Psoralen Photoactivation(PARA)

Received 1 August 2001; accepted 14 November 2001 ABSTRACT

The genetic disease Fanconi anemia (FA), generally considered to be a DNA repair defect, has also been related to a deficiency in cellular defense against reactive oxygen species (ROS). Results show that mitochondrial matrix densification occurs rapidly and transiently in FA fibroblasts following 8-methoxypsoralen (8-MOP) photoreaction or ultraviolet A (320 to 380 nm) (UVA) irradiation. This effect is oxygen dependent because it is more important under 20 than under 5 % oxygen tension. In contrast, in normal fibroblasts very little, if any, densification of mitochondrial matrix is induced by treatments even at the highest oxygen tension. The changes in matrix density in FA cells are accompanied by some modifications in transmembrane potential, linked to a Fenton-like reaction, and in mitochondrial cardiolipin content, differing from the responses of normal cells. These data are indicative of some sort of membrane damage induced by 8-MOP photoreaction and UVA irradiation, to which FA cells appear to be particularly sensitive.

Abbreviations: DESF, iron chelator deferoxamine; DiOC^sub 6^(3), 3,3'dihexyloxacarbocyanine iodide; FA, Fanconi anemia; mCICCP, carbamoyl cyanide m-chlorophenylhydrazone; 8-MOP, 8-methoxypsoralen; NAO, 10-N-nonyl-3,6-bis(dimethylamino)acridine (10-N-nonyl acridine orange); ^sup 1^O^sub 2^ singlet molecular oxygen; OD, optical density; OH, hydroxyl radical; PBS, phosphate-buffered saline; ROS, reactive oxygen species; TNF(alpha), tumor necrosis factor(alpha); UVA, ultraviolet radiation in the A region (320 to 380 nm); Delta Psi ^sub m^ mitochondrial transmembrane potential.

INTRODUCTION Fanconi anemia (FA) is an autosomal recessive disorder characterized by progressive pancytopenia associated with multiple developmental abnormalities, and cancer proneness (1). Eight different complementation groups, FA-A to FA-G, are actually distinguished (2,3), and six genes are cloned: FANCA, FANCC, FANCD2, FANCE, FANCG and FANCF. However, the precise functions) of the multiprotein FA complex are still unknown (4). FA cells demonstrate an increased sensitivity to DNA cross-linking agents such as psoralen plus ultraviolet A (320 to 380 nm) (UVA), chromosomal instability, a G2 cell cycle delay, modifications of some cytokine expression and of the apoptotic response (for review, see D'Andrea and Grompe [51).

Although FA is generally considered to be a DNA repair defect (for reviews, see Clarke et al. [61 and Buchwald and Moustacchi [71), some of the metabolic disturbances reported also suggest anomalies in oxygen metabolism (8,9). For instance, FA cells demonstrate an increased activity of the antioxidant phospholipid-hydroperoxide-gluthatione-peroxidase and a constitutive induction of the factor nuclear factor-K B, despite a reduced oxygen consumption (10), indicating an elevated cellular level of reactive oxygen species (ROS), either by overproduction or by diminished detoxification. Moreover, an oxidative stress to FA cells results in an increased production of ROS and accumulation of 8-hydroxy-2'-deoxyguanosine in the DNA (11).

Acknowledgements-We thank Dr. Patrice Xavier Petit for helpful

advice about specific mitochondrion fluorochromes. We are very grateful to Dr. Pierre Rustin for critically reading the manuscript and to Yuval Cohen for English language advice. We are very grateful to Prof. M. Grompe and Dr. B. Cox for determination of the complementation group of FA 150 fibroblasts. The technical contributions of Elly Efthymiou and Michele Guggiari are gratefully acknowledged. S.R. thanks particularly Drs. Giuseppe Baldacci and Evelyne Sage for their welcome in UMR 2027 CNRS/IC. This work was supported by grants from CNRS, Institut Curie, ACC SV n(deg) 8 (Ministere de la Recherche, France).

(PARA)Posted on the web site on November 28, 2001.

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Solange Rousset*1, Silvano Nocentini1, Danielle Rouillard2, Christiane Baroche1 and Ethel Moustacchi1

1UMR 218 CNRS, Institut Curie-Recherche, Paris, France and 2Laboratoire de Cytometrie, Institut Curie-Recherche, Paris, France

*To whom correspondence should be addressed at: UMR 2027 CNRS, Institut Curie-Recherche, Batiment 110, Centre Universitaire, 91405 Orsay Cedex, France. Fax: 33-1-6986-9429; e-mail: solange.rousset@ curie.u-psud.fr

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