Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome.
Nijmegen breakage syndrome (NBS) is an autosomal recessive chromosomal instability syndrome characterized by microcephaly, growth retardation, immunodeficiency, and cancer predisposition. Cells from NBS patients are hypersensitive to ionizing radiation with cytogenetic features indistinguishable from ataxia telangiectasia. We describe the positional cloning of a gene encoding a novel protein, nibrin. It contains two modules found in cell cycle checkpoint proteins, a forkhead-associated domain adjacent to a breast cancer carboxy-terminal domain. A truncating 5 bp deletion was identified in the majority of NBS patients, carrying a conserved marker haplotype. Five further truncating mutations were identified in patients with other distinct haplotypes. The domains found in nibrin and the NBS phenotype suggest that this disorder is caused by defective responses to DNA double-strand breaks.
Varon
R
R
Institute of Human Genetics, Charité Humboldt University, Berlin, Germany.
Vissinga
C
C
Platzer
M
M
Cerosaletti
K M
KM
Chrzanowska
K H
KH
Saar
K
K
Beckmann
G
G
Seemanová
E
E
Cooper
P R
PR
Nowak
N J
NJ
Stumm
M
M
Weemaes
C M
CM
Gatti
R A
RA
Wilson
R K
RK
Digweed
M
M
Rosenthal
A
A
Sperling
K
K
Concannon
P
P
Reis
A
A
D000595:Amino Acid Sequence; D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000235:genetics*; D002869:Chromosome Aberrations / Q000235:genetics; D019457:Chromosome Breakage / Q000235:genetics*; D025063:Chromosome Disorders; D002874:Chromosome Mapping; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D003001:Cloning, Molecular / Q000379:methods; D004249:DNA Damage; D004260:DNA Repair; D005260:Female; D018703:Founder Effect; D005808:Genes, Recessive / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008831:Microcephaly / Q000235:genetics*; D008969:Molecular Sequence Data; D009687:Nuclear Proteins; D012333:RNA, Messenger / Q000032:analysis; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D013577:Syndrome
D018797:Cell Cycle Proteins; C112156:NBN protein, human; D009687:Nuclear Proteins; D012333:RNA, Messenger