POLA1 encodes the catalytic unit of DNA polymerase α, which together with the Primase complex launches the DNA replication process. While complete deficiency of this essential gene is presumed to be lethal, at least two conditions due to partial POLA1 deficiency have been described. The first genetic syndrome to be mapped to POLA1 was X-linked reticulate pigmentary disorder (XLPDR, MIM #301220), a rare syndrome characterized by skin hyperpigmentation, sterile multiorgan inflammation, recurrent infections, and distinct facial features. XLPDR has been shown to be accompanied by profound activation of type I interferon signaling, but unlike other interferonopathies, it is not associated with autoantibodies or classical autoimmunity. Rather, it is accompanied by marked Natural Killer (NK) cell dysfunction, which may explain the recurrent infections seen in this syndrome. To date, all XLPDR cases are caused by the same recurrent intronic mutation, which results in gene missplicing. Several hypomorphic mutations in POLA1, distinct from the XLPDR intronic mutation, have been recently reported and these mutations associate with a separate condition, van Esch–O’Driscoll syndrome (VEODS, MIM #301030). This condition results in growth retardation, microcephaly, hypogonadism, and in some cases, overlapping immunological features to those seen in XLPDR. This review summarizes our current understanding of the clinical manifestations of POLA1 gene mutations with an emphasis on its immunological consequences, as well as recent advances in understanding of its pathophysiologic basis and potential therapeutic options.

POLA1编码 DNA 聚合酶 α 的催化单元，它与 Primase 复合物一起启动 DNA 复制过程。虽然这种必需基因的完全缺乏被认为是致命的，但由于部分POLA1缺乏，至少有两种情况已经被描述。第一个被映射到POLA1的遗传综合征是 X 连锁网状色素障碍 (XLPDR, MIM #301220)，一种以皮肤色素沉着过度、无菌性多器官炎症、反复感染和明显面部特征为特征的罕见综合征。XLPDR 已被证明伴随着 I 型干扰素信号的深度激活，但与其他干扰素病不同，它与自身抗体或经典自身免疫无关。相反，它伴随着明显的自然杀伤 (NK) 细胞功能障碍，这可能解释了这种综合征中出现的反复感染。迄今为止，所有 XLPDR 病例都是由相同的复发性内含子突变引起的，这会导致基因错接。POLA1中的几个亚型突变最近报道了与 XLPDR 内含子突变不同的突变，这些突变与另一种疾病 van Esch-O'Driscoll 综合征 (VEODS, MIM #301030) 相关。这种情况会导致生长迟缓、小头畸形、性腺机能减退，并且在某些情况下，免疫学特征与 XLPDR 中所见的重叠。这篇综述总结了我们目前对POLA1基因突变临床表现的理解，重点是其免疫学后果，以及对其病理生理基础和潜在治疗选择的理解的最新进展。