Cottineau Julien, Kottemann Molly C, Lach Francis P, Kang Young-Hoon, Vély Frédéric, Deenick Elissa K, Lazarov Tomi, Gineau Laure, Wang Yi, Farina Andrea, Chansel Marie, Lorenzo Lazaro, Piperoglou Christelle, Ma Cindy S, Nitschke Patrick, Belkadi Aziz, Itan Yuval, Boisson Bertrand, Jabot-Hanin Fabienne, Picard Capucine, Bustamante Jacinta, Eidenschenk Céline, Boucherit Soraya, Aladjidi Nathalie, Lacombe Didier, Barat Pascal, Qasim Waseem, Hurst Jane A, Pollard Andrew J, Uhlig Holm H, Fieschi Claire, Michon Jean, Bermudez Vladimir P, Abel Laurent, de Villartay Jean-Pierre, Geissmann Frédéric, Tangye Stuart G, Hurwitz Jerard, Vivier Eric, Casanova Jean-Laurent, Smogorzewska Agata, Jouanguy Emmanuelle
J Clin Invest. 2017 May 1;127(5):1991-2006. doi: 10.1172/JCI90727. Epub 2017 Apr 17.
Inborn errors of DNA repair or replication underlie a variety of clinical phenotypes. We studied 5 patients from 4 kindreds, all of whom displayed intrauterine growth retardation, chronic neutropenia, and NK cell deficiency. Four of the 5 patients also had postnatal growth retardation. The association of neutropenia and NK cell deficiency, which is unusual among primary immunodeficiencies and bone marrow failures, was due to a blockade in the bone marrow and was mildly symptomatic. We discovered compound heterozygous rare mutations in Go-Ichi-Ni-San (GINS) complex subunit 1 (GINS1, also known as PSF1) in the 5 patients. The GINS complex is essential for eukaryotic DNA replication, and homozygous null mutations of GINS component-encoding genes are embryonic lethal in mice. The patients' fibroblasts displayed impaired GINS complex assembly, basal replication stress, impaired checkpoint signaling, defective cell cycle control, and genomic instability, which was rescued by WT GINS1. The residual levels of GINS1 activity reached 3% to 16% in patients' cells, depending on their GINS1 genotype, and correlated with the severity of growth retardation and the in vitro cellular phenotype. The levels of GINS1 activity did not influence the immunological phenotype, which was uniform. Autosomal recessive, partial GINS1 deficiency impairs DNA replication and underlies intra-uterine (and postnatal) growth retardation, chronic neutropenia, and NK cell deficiency.
DNA修复或复制的先天性缺陷是多种临床表型的基础。我们研究了来自4个家族的5名患者，他们均表现出宫内生长迟缓、慢性中性粒细胞减少和自然杀伤（NK）细胞缺陷。5名患者中有4名还存在出生后生长迟缓。中性粒细胞减少和NK细胞缺陷的关联在原发性免疫缺陷和骨髓衰竭中并不常见，其原因是骨髓中的阻滞，且症状较轻。我们在这5名患者中发现了Go-Ichi-Ni-San（GINS）复合体亚基1（GINS1，也称为PSF1）的复合杂合罕见突变。GINS复合体对真核生物DNA复制至关重要，在小鼠中，编码GINS成分的基因的纯合无效突变是胚胎致死性的。患者的成纤维细胞表现出GINS复合体组装受损、基础复制应激、检查点信号传导受损、细胞周期控制缺陷和基因组不稳定，而野生型GINS1可挽救这些情况。根据患者的GINS1基因型，患者细胞中GINS1活性的残留水平达到3%至16%，并且与生长迟缓的严重程度和体外细胞表型相关。GINS1活性水平不影响免疫表型，免疫表型是一致的。常染色体隐性、部分GINS1缺陷会损害DNA复制，并导致宫内（和出生后）生长迟缓、慢性中性粒细胞减少和NK细胞缺陷。
