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.

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