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

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

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  • NSTL
  • Springer Nature
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.

HOMOLOGOUS RECOMBINATIONCRYSTAL-STRUCTUREGENETIC-VARIANTSATPASE ACTIVITYDNA-BINDINGPROTEINFILAMENTINHIBITORDISEASEREPAIR

Ameziane, Najim、May, Patrick、Haitjema, Anneke、van de Vrugt, Henri J.、van Rossum-Fikkert, Sari E.、Ristic, Dejan、Williams, Gareth J.、Balk, Jesper、Rockx, Davy、Li, Hong、Rooimans, Martin A.、Oostra, Anneke B.、Velleuer, Eunike、Dietrich, Ralf、Bleijerveld, Onno B.、Altelaar, A. F. Maarten、Meijers-Heijboer, Hanne、Joenje, Hans、Glusman, Gustavo、Roach, Jared、Hood, Leroy、Galas, David、Wyman, Claire、Balling, Rudi、den Dunnen, Johan、de Winter, Johan P.、Kanaar, Roland、Gelinas, Richard、Dorsman, Josephine C.

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Vrije Univ Amsterdam, Med Ctr, Dept Clin Genet, NL-1081 BT Amsterdam, Netherlands

Luxembourg Ctr Syst Biomed, L-4362 Esch Sur Alzette, Luxembourg

Canc Genom Ctr, Dept Genet, NL-3000 CA Rotterdam, Netherlands

Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Berkeley, CA 94720 USA

Inst Syst Biol, Seattle, WA 98109 USA

Univ Dusseldorf, Fac Med, Ctr Child & Adolescent Hlth, Dept Paediat Oncol Hematol & Clin Immunol, D-40225 Dusseldorf, Germany

Deutsch Fanconi Anam Hilfe eV, D-59427 Unna, Germany

Netherlands Canc Inst, Mass Spectrometry & Prote Facil, NL-1066 CX Amsterdam, Netherlands

Leiden Univ, Med Ctr, Dept Human & Clin Genet, NL-2333 ZA Leiden, Netherlands

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2015

10.1038/ncomms9829

Nature Communications

Nature Communications

AHCI
ISSN：2041-1723
年,卷(期)：2015.6(Dec.)
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