Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency

Abstract

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.

Emerging insights into human health and NK cell biology from the study of NK cell deficiencies

“…Like the MCM4‐deficient patients, they also had some extra‐immune manifestations including short stature and dysmorphic features. Whole exome sequencing identified mutations in GINS1 , leading to decreased protein expression of GINS1 and other GINS complex members . As with MCM4 mutations, biochemical analysis demonstrated impaired initiation of DNA replication in patient fibroblasts, and cells containing damaging GINS1 variants had cell cycle arrest and induction of DNA damage repair pathways measured by γH2AX staining.…”

“…Given the rarity of NKD, there is an increasingly strong signal around the theme of genes associated with cell cycle and proliferation in NKD. Mutations in MCM4 and GINS1 all lead to a strikingly similar NK cell phenotype with seemingly little involvement of other lymphocyte lineages . While less well described, mutations in other DNA replication and repair enzymes also lead to NK cell aberrations, including RTEL1 , ZBTB24 , and POLE2 …”

“…This could account for the delayed onset, in some cases well into adulthood, of NKD that could affect the stem cell subset, particularly GATA2 deficiency. It is also important to consider the natural history of exposure to herpesviral infections as a driver of NK cell subsets and activation/maturation, particularly as many of these happen in adolescence and likely account for the timing of appearance of symptoms, particularly in patients with IRF8 and CMG helicase mutations …”

Dormant origins as a built-in safeguard in eukaryotic DNA replication against genome instability and disease development

“…The etiology of NK cell deficiency was also linked with mutations in GINS1 , which encodes a subunit of CMG helicase [153]. More interestingly, a missense variant in MCM2 has been described to be associated with a dominant disorder characterized by progressive hearing loss [154].…”

Defects in DNA replication hit NK cells and neutrophils

“…Cottineau et al determined that the amount of GINS1 expressed in patientderived cells ranges from 29% to 53% of the level of GINS1 generated by cells from healthy controls (1). This reduced expression apparently leads to decreased expression of GINS3 and GINS4, resulting in defective GINS complex assembly.…”