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

N Ameziane, P May, A Haitjema, HJ van de Vrugt, SE van Rossum-Fikkert, D. Ristic, GJ Williams, J Balk, D Rockx, H Li, MA Rooimans, AB Oostra, E Velleuer, R Dietrich, OB (Onno) Bleijerveld, AFM Altelaar, H Meijers-Heijboer, H Joenje, G Glusman, J RoachL Hood, D Galas, C.L. Wyman, R Balling, J den Dunnen, JP (Johan) de Winter, Roland Kanaar, R Gelinas, JC Dorsman

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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.
Original languageUndefined/Unknown
JournalNature Communications
Volume6
DOIs
Publication statusPublished - 2015

Research programs

  • EMC MGC-01-12-03
  • EMC MM-03-32-04

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