Recessive mutations in MCM4/PRKDC cause a novel syndrome involving a primary immunodeficiency and a disorder of DNA repair
Recessive mutations in MCM4/PRKDC cause a novel syndrome involving a primary immunodeficiency and a disorder of DNA repair
复制标题
DOI：
10.1136/jmedgenet-2012-100803
复制
发表时间：
2012-04-01
影响因子：
4
通讯作者：
Ennis, Sean
中科院分区：
文献类型：
--
作者：
Casey, Jillian P.;Nobbs, Michael;Ennis, Sean
背景：一项研究介绍了10名患有一种新综合征的儿童，他们的父母是来自爱尔兰旅行者人群的近亲。该综合征的特征是自然杀伤（NK）细胞缺乏，非典型范可尼型DNA断裂障碍的证据，以及家族性糖皮质激素缺乏症（FGD）的特征。NK细胞缺乏可能是患者反复出现病毒性疾病的原因。分子测试支持马赛克范可尼贫血的诊断，但患者不存在任何预期的疾病临床特征。FGD的症状表现延迟发作，可能是继发表型。由于所有三种表型分离在一起，作者推测，NK细胞缺陷，DNA修复障碍和FGD是由一个单一的隐性遗传events.Methods单核苷酸多态性纯合性作图和有针对性的下一代测序的10例患者和16名未受影响的亲属。对候选区域的靶向重测序显示，在所有10个受影响的个体中，MCM4/PRKDC均存在纯合突变。与观察到的DNA断裂障碍一致，MCM4和PRKDC都参与ATM/ATR（共济失调-毛细血管扩张-突变/ATM-Rad 3相关）DNA修复途径，这在范可尼贫血患者中是有缺陷的。结论MCM4/PRKDC基因突变是导致DNA断裂和NK细胞缺陷的新原因。这些发现表明，临床医生应该考虑这种疾病的患者未能茁壮成长，谁开发色素沉着或复发性感染。
Background A study is presented of 10 children with a novel syndrome born to consanguineous parents from the Irish Traveller population. The syndrome is characterised by a natural killer (NK) cell deficiency, evidence of an atypical Fanconi's type DNA breakage disorder, and features of familial glucocorticoid deficiency (FGD). The NK cell deficiency probably accounts for the patients' recurrent viral illnesses. Molecular tests support a diagnosis of mosaic Fanconi's anaemia, but the patients do not present with any of the expected clinical features of the disorder. The symptomatic presentation of FGD was delayed in onset and may be a secondary phenotype. As all three phenotypes segregate together, the authors postulated that the NK cell deficiency, DNA repair disorder and FGD were caused by a single recessive genetic event.Methods Single-nucleotide polymorphism homozygosity mapping and targeted next-generation sequencing of 10 patients and 16 unaffected relatives.Results A locus for the syndrome was identified at 8p11.21-q11.22. Targeted resequencing of the candidate region revealed a homozygous mutation in MCM4/PRKDC in all 10 affected individuals. Consistent with the observed DNA breakage disorder, MCM4 and PRKDC are both involved in the ATM/ATR (ataxia-telangiectasia-mutated/ATM-Rad 3-related) DNA repair pathway, which is defective in patients with Fanconi's anaemia. Deficiency of PRKDC in mice has been shown to result in an abnormal NK cell physiology similar to that observed in these patients.Conclusion Mutations in MCM4/PRKDC represent a novel cause of DNA breakage and NK cell deficiency. These findings suggest that clinicians should consider this disorder in patients with failure to thrive who develop pigmentation or who have recurrent infections.