Pan Qiang, Petit-Frére Corinne, Lähdesmäki Aleksi, Gregorek Hanna, Chrzanowska Krystyna H, Hammarström Lennart
Division of Clinical Immunology, IMPI, Karolinska Institutet at Huddinge Hospital, and Center for Biotechnology and Center for Oral Biology, NOVUM, Huddinge, Sweden.
Eur J Immunol. 2002 May;32(5):1300-8. doi: 10.1002/1521-4141(200205)32:5<1300::AID-IMMU1300>3.0.CO;2-L.
Ataxia-Telangiectasia (A-T) and Nijmegen breakage syndrome (NBS) are recessive genetic diseases with similar cellular phenotypes that are caused by mutations in the recently described ATM (encoding ATM) and NBS1 (encoding p95) genes, respectively. Both disorders are accompanied by immunodeficiency in a majority of patients, but the mechanism involved has as yet not been established. We demonstrate that in cells from A-T patients, the switch (S) recombination junctions are aberrant and characterized by a strong dependence on short sequence homologies and devoid of normally occurring mutations around the breakpoint. A low number of S fragments were generated in cells from NBS patients and showed only limited dependence on sequence identity and mutation frequencies were similar to those observed in normal controls. We propose that ATM and p95 are both involved in the final step(s) in class switch recombination with related, but disparate, functional roles. Thus, the general pathway involved in DNA repair also has a major influence on the immunoglobulin isotype switching process.
共济失调毛细血管扩张症（A-T）和尼曼匹克氏症（NBS）是隐性遗传疾病，具有相似的细胞表型，分别由最近发现的ATM（编码ATM）和NBS1（编码p95）基因突变引起。这两种疾病在大多数患者中都伴有免疫缺陷，但其中涉及的机制尚未明确。我们证明，在A-T患者的细胞中，转换（S）重组连接点异常，其特征是强烈依赖短序列同源性，且在断点周围没有正常出现的突变。NBS患者的细胞中产生的S片段数量较少，仅显示出对序列同一性的有限依赖，且突变频率与正常对照中观察到的相似。我们提出，ATM和p95都参与了类别转换重组的最后步骤，具有相关但不同的功能作用。因此，DNA修复所涉及的一般途径也对免疫球蛋白同种型转换过程有重大影响。
