DNA replication is fundamental for cell proliferation in all organisms. Nonetheless, components of the replisome have been implicated in human disease, and here we report PRIM1 encoding the catalytic subunit of DNA primase as a novel disease gene. Using a variant classification agnostic approach, biallelic mutations in PRIM1 were identified in five individuals. PRIM1 protein levels were markedly reduced in patient cells, accompanied by replication fork asymmetry, increased interorigin distances, replication stress, and prolonged S-phase duration. Consequently, cell proliferation was markedly impaired, explaining the patients’ extreme growth failure. Notably, phenotypic features distinct from those previously reported with DNA polymerase genes were evident, highlighting differing developmental requirements for this core replisome component that warrant future investigation.

中文翻译：

---

PRIM1缺乏会导致一种独特的原始侏儒症综合征

DNA复制是所有生物体细胞增殖的基础。尽管如此，复制体的成分与人类疾病有关，我们在这里报告PRIM1将 DNA 引发酶的催化亚基编码为一种新的疾病基因。使用变异分类不可知的方法，在五个个体中鉴定了 PRIM1 中的双等位基因突变。患者细胞中 PRIM1 蛋白水平显着降低，伴随着复制叉不对称、原点间距离增加、复制压力和 S 期持续时间延长。因此，细胞增殖明显受损，这解释了患者极度生长失败的原因。值得注意的是，与先前报道的 DNA 聚合酶基因不同的表型特征是明显的，突出了这一核心复制体成分的不同发育要求，值得未来研究。