PDF(Pubmed)
Abstract：
Mutations in genes of the DNA polymerase complex have been linked to impaired immunological function next to distinct syndromic features. Biallelic mutations in PRIM1 are associated with a primordial dwarfism syndrome with variable hypogammaglobulinemia. The disease is mostly lethal in infancy due to pulmonary infections as well as hepatic cirrhosis. We studied 3 novel patients with PRIM1-deficiency with a focus on immunological consequences. All three shared dysmorphic features including a prominent forehead, triangular face and bilateral cryptorchidism. P1 carried the novel homozygous PRIM1 splice variant c.103+2T>G, allowing residual protein expression and associated with a mild clinical phenotype. P2 and P3 carried the known homozygous variant c.638+36C>G and died in infancy. Paradoxically, B cell lymphopenia was most pronounced in P1. No other significant lymphocyte abnormalities were detected. Interestingly, all 3 patients showed variable, but intermittently excessive Type I interferon signatures. In summary, the B-cell deficiency in PRIM1-deficiency is markedly variable and the severity of syndromic manifestations is not predictive of the immunological phenotype. We highlight a potential contribution of pathological type I interferon activation to disease pathogenesis which warrants further investigations.
摘要：
DNA聚合酶复合物基因的突变与独特的综合征特征旁边的受损的免疫功能有关。PRIM1的双等位基因突变与具有可变低丙种球蛋白血症的原始侏儒症综合征相关。由于肺部感染以及肝硬化，该疾病在婴儿期大部分是致命的。我们研究了3例PRIM1缺乏症的新患者，重点是免疫学后果。所有三个共有的畸形特征，包括突出的前额，三角脸和双侧隐睾。P1携带新的纯合PRIM1剪接变体c.103+2T>G，允许残留蛋白表达并与轻度临床表型相关。P2和P3携带已知的纯合变体c.638+36C>G并在婴儿期死亡。矛盾的是,B细胞淋巴细胞减少在P1中最为明显。未检测到其他显著的淋巴细胞异常。有趣的是,所有3例患者都表现出不同的，而是间歇性过度的I型干扰素特征。总之,PRIM1缺乏症中的B细胞缺乏是显著可变的,综合征表现的严重程度不能预测免疫学表型.我们强调了病理I型干扰素激活对疾病发病机理的潜在贡献，值得进一步研究。
