Positional cloning of the gene for Nijmegen breakage syndrome

• DOI: 10.1038/549
• Publication Date: 2002-07-26T08:32:58Z
• Authors: Shinya Matsuura; Hiroshi Tauchi; Asako Nakamura; Noriko Kondo; Shuichi Sakamoto; Satoru Endo; Dominique Smeets; Brigitte Solder; Bernd H. Belohradsky; Vazken M. Der Kal...; Mitsuo Oshimura; Minoru Isomura; Yusuke Nakamura; Kenshi Komatsu
• Keywords: Breuk-gevoelige plaatsen in chromosomen bij de mens; 0301 basic medicine; Databases, Factual; (Fragile) breakage-prone sites in human chromosomes; Molecular Sequence Data; Chromosome Mapping; Nuclear Proteins; Cell Cycle Proteins; Chromosome Breakage; Syndrome; Pedigree; 3. Good health; Ataxia Telangiectasia; 03 medical and health sciences; Microcephaly; Humans; Severe Combined Immunodeficiency; Amino Acid Sequence; Cloning, Molecular; Growth Disorders; Chromosomes, Human, Pair 8

Nijmegen breakage syndrome (NBS), also known as ataxia-telangiectasia (AT) variant, is an autosomal recessive disorder characterized by microcephaly, growth retardation, severe combined immunodeficiency and a high incidence of lymphoid cancers. Cells from NBS patients display chromosome instability, hypersensitivity to ionizing radiation and abnormal cell-cycle regulation after irradiation, all of which are characteristics shared with AT. Recently, the NBS locus was mapped at 8q21 by two independent approaches, complementation studies and linkage analysis. Here, we report the positional cloning of the NBS gene, NBS1, from an 800-kb candidate region. The gene comprises 50 kb and encodes a protein of 754 amino acids. The amino-terminal region of the protein shows weak homology to the yeast XRS2, MEK1, CDS1 and SPK1 proteins. The gene is expressed at high levels in the testes, suggesting that it might be involved in meiotic recombination. We detected the same 5-bp deletion in 13 individuals, and conclude that it is likely to be a founder mutation.