1. ¹Department of Biochemistry and Biophysics 'F Cedrangolo' II University of Naples, Naples, Italy
2. ²Bone Marrow Transplantation Centre, 'S Camillo – Forlanini' Hospital, Rome, Italy
3. ³Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy
4. ⁴Department of Experimental Medicine and Pathology, University 'La Sapienza' of Rome, Rome, Italy
5. ⁵Department of Genetics, 'Elena d'Aosta Hospital', ASL Napoli 1, Naples, Italy
6. ⁶Medical Genetics, Department of Reproductive and Developmental Sciences, IRCCS Burlo Garofolo Hospital, University of Trieste, Trieste, Italy
7. ⁷Department of Experimental Oncology, National Institute of Cancer, Milan, Italy

Correspondence: Professor A Savoia, Medical Genetics, Department of Reproductive and Developmental Sciences, IRCCS Burlo Garofolo Hospital, University of Trieste, via dell'Istria, 65/1 – 34137 Trieste, Italy. E-mail: savoia@burlo.trieste.it

Received 30 July 2006; Revised 20 September 2006; Accepted 28 September 2006; Published online 9 November 2006.

Abstract

Fanconi anemia (FA) is an autosomal recessive disease characterized by pancitopenia, congenital malformations, predisposition to cancers and chromosomal instability. We report the clinical and molecular features of a patient initially identified as a potential FA case only because of chemotherapy toxicity during the treatment of a T-lineage acute lymphoblastic leukemia (ALL). Cells from this patient showed a moderate chromosomal instability, increasing sensitivity to DNA crosslinking agents but normal response to ionizing radiation. The analysis of FA proteins demonstrated a marked reduction of FANCD2 (>95%), but normal levels of FANCA or FANCG. Interestingly, this defect was associated with a homozygous missense mutation of FANCD2, resulting in a novel amino-acid substitution (Leu153Ser) at residue Leu153, which is highly conserved through evolution. The FANCD2^L153S protein, whose reduced expression was not due to impaired transcription, was detected also in its monoubiquitinated form in the nucleus, suggesting that the mutation does not affect post-translation modifications or subcellular localization but rather the stability of FANCD2. Therefore, the hypomorphic Leu153Ser mutation represents the first example of a FANCD2 defect that might promote clonal progression of tumors, such as T-ALL, and severe chemotherapy toxicity in patients without any clinical manifestations typical of FA.