A novel Fanconi anaemia subtype associated with a dominant-negative mutation in RAD51

  • Nat Commun. 2015 Dec 18;6:8829. doi: 10.1038/ncomms9829.
Najim Ameziane  1 ,  Patrick May  2  3 ,  Anneke Haitjema  1 ,  Henri J van de Vrugt  1  4 ,  Sari E van Rossum-Fikkert  5  6 ,  Dejan Ristic  5  6 ,  Gareth J Williams  7 ,  Jesper Balk  1 ,  Davy Rockx  1 ,  Hong Li  3 ,  Martin A Rooimans  1 ,  Anneke B Oostra  1 ,  Eunike Velleuer  8 ,  Ralf Dietrich  9 ,  Onno B Bleijerveld  10 ,  A F Maarten Altelaar  10 ,  Hanne Meijers-Heijboer  1 ,  Hans Joenje  1 ,  Gustavo Glusman  3 ,  Jared Roach  3 ,  Leroy Hood  3 ,  David Galas  2  11 ,  Claire Wyman  5  6 ,  Rudi Balling  2 ,  Johan den Dunnen  12 ,  Johan P de Winter  1 ,  Roland Kanaar  5  6 ,  Richard Gelinas  3 ,  Josephine C Dorsman  1
Affiliations
  • 1. Department of Clinical Genetics, VU University Medical Center, Van der Boechorststraat 7, Amsterdam 1081 BT, The Netherlands.
  • 2. Luxembourg Centre for Systems Biomedicine, House of Biomedicine, 7 Avenue des Hauts-Fourneaux, Esch/Alzette L-4362, Luxembourg.
  • 3. Institute for Systems Biology, 401 Terry Avenue North, Seattle, Washington 98109-5234, USA.
  • 4. Division of Biological Stress Response, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066 CX, The Netherlands.
  • 5. Department of Genetics, Cancer Genomics Center, PO Box 2040, Rotterdam 3000 CA, The Netherlands.
  • 6. Department of Radiation Oncology, Erasmus Medical Center, PO Box 2040, Rotterdam 3000 CA, The Netherlands.
  • 7. Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, California 94720, USA.
  • 8. Department of Paediatric Oncology, Hematology and Clinical Immunology, Center for Child and Adolescent Health, Medical Faculty, Heinrich Heine University, Moorenstrasse 5, 40225 Du¨sseldorf, Germany.
  • 9. Deutsche Fanconi-Anämie-Hilfe e.V., Böckenweg 4, 59427 Unna, Germany.
  • 10. Mass Spectrometry and Proteomics Facility, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066 CX, The Netherlands.
  • 11. Pacific Northwest Diabetes Research Institute, 720 Broadway, Seattle, Washington 98122, USA.
  • 12. Department of Human and Clinical Genetics, Leiden University Medical Center, Albinusdreef 2, Leiden 2333ZA, The Netherlands.
PMID: 26681308 DOI: 10.1038/ncomms9829
Abstract

Fanconi anaemia (FA) is a hereditary disease featuring hypersensitivity to DNA cross-linker-induced chromosomal instability in association with developmental abnormalities, bone marrow failure and a strong predisposition to Cancer. A total of 17 FA disease genes have been reported, all of which act in a recessive mode of inheritance. Here we report on a de novo g.41022153G>A; p.Ala293Thr (NM_002875) missense mutation in one allele of the homologous recombination DNA repair gene RAD51 in an FA-like patient. This heterozygous mutation causes a novel FA subtype, 'FA-R', which appears to be the first subtype of FA caused by a dominant-negative mutation. The patient, who features microcephaly and mental retardation, has reached adulthood without the typical bone marrow failure and paediatric cancers. Together with the recent reports on RAD51-associated congenital mirror movement disorders, our results point to an important role for RAD51-mediated homologous recombination in neurodevelopment, in addition to DNA repair and Cancer susceptibility.