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

被引：115

作者：

Ameziane, Najim ^{[1
]}

May, Patrick ^{[2
,3
]}

Haitjema, Anneke ^{[1
]}

van de Vrugt, Henri J. ^{[1
,4
]}

van Rossum-Fikkert, Sari E. ^{[5
,6
]}

Ristic, Dejan ^{[5
,6
]}

Williams, Gareth J. ^{[7
]}

Balk, Jesper ^{[1
]}

Rockx, Davy ^{[1
]}

Li, Hong ^{[3
]}

Rooimans, Martin A. ^{[1
]}

Oostra, Anneke B. ^{[1
]}

Velleuer, Eunike ^{[8
]}

Dietrich, Ralf ^{[9
]}

Bleijerveld, Onno B. ^{[10
]}

Altelaar, A. F. Maarten ^{[10
]}

Meijers-Heijboer, Hanne ^{[1
]}

Joenje, Hans ^{[1
]}

Glusman, Gustavo ^{[3
]}

Roach, Jared ^{[3
]}

Hood, Leroy ^{[3
]}

Galas, David ^{[2
,11
]}

Wyman, Claire ^{[5
,6
]}

Balling, Rudi ^{[2
]}

den Dunnen, Johan ^{[12
]}

de Winter, Johan P. ^{[1
]}

Kanaar, Roland ^{[5
,6
]}

Gelinas, Richard ^{[3
]}

Dorsman, Josephine C. ^{[1
]}

机构：

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

[2] Luxembourg Ctr Syst Biomed, L-4362 Esch Sur Alzette, Luxembourg

[3] Inst Syst Biol, Seattle, WA 98109 USA

[4] Netherlands Canc Inst, Div Biol Stress Response, NL-1066 CX Amsterdam, Netherlands

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

[6] Erasmus MC, Dept Radiat Oncol, NL-3000 CA Rotterdam, Netherlands

[7] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Berkeley, CA 94720 USA

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

[9] Deutsch Fanconi Anam Hilfe eV, D-59427 Unna, Germany

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

[11] Pacific Northwest Diabet Res Inst, Seattle, WA 98122 USA

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

来源：

NATURE COMMUNICATIONS | 2015年 / 6卷

关键词：

HOMOLOGOUS RECOMBINATION; CRYSTAL-STRUCTURE; DNA; PROTEIN; REPAIR; GENE;

D O I：

10.1038/ncomms9829

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：11

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