Biology subjects

Ahn, Y.-O.

Publications and source records attributed to Ahn, Y.-O..

4 recordsLinked to original sources

bioRxiv2026

Autosomal dominant CDC45 deficiency with allelic expression bias causes a novel genetic disease of the immune system

Here we describe a damaging heterozygous variant in CDC45 in an individual with common variable immunodeficiency (CVID) and recurrent viral infections. This individual has variably decreased number of circulating NK cells, disruption in the ratio of CD56bright to CD56dim cells, and consistently decreased NK cell function. Interestingly, the inherited CDC45 variant is also present in a sibling with less severe clinical manifestations; we determined that allelic bias of the damaging allele accounts for this differential expressivity. As previously reported for other helicase variants that cause inborn errors of immunity (IEI), we found cell cycle defects in immune cells from the proband that lead to reduced survival of NK cells. Together, these findings link another member of the core replicative helicase complex to inborn errors of immunity and highlight the sensitivity of NK cells to these variants. They also define another case of allelic bias contributing to variable expressivity of an IEI gene.

immunology↗

bioRxiv2023

iPSC-based modeling of helicase deficiency reveals impaired cell proliferation and increased apoptosis after NK cell lineage commitment

While monogenic variants in CDC45-MCM-GINS (CMG) replisome proteins cause human natural killer cell deficiencies (NKD), family members with the same inherited variants often have variable clinical and cellular phenotypes. We investigated two siblings with inherited compound heterozygous GINS4 variants but variable disease expressivity. Cell cycle impairment and increased apoptosis were detected following NK cell lineage commitment but not in pluripotent cells. While this effect was detected in both siblings, the efficiency of NK cell differentiation was variable and correlated with differential clinical severity of NKD. Further investigation of allelic expression of inherited GINS4 variants demonstrated expected biallelic expression of GINS4 in pluripotent cells and progenitors. However, allelic bias in lineage-committed NK cells led to over- or under-representation of more damaging GINS4 heterozygous variants associated with differential cellular and clinical severity. This study identifies allelic bias that causes phenotypic variation of monogenic diseases and defines mechanisms underlying immunodeficiency.

cell biology↗

bioRxiv2023

Replication stress in activated human NK cells induces sensitivity to apoptosis

Natural killer cells are innate immune effectors that kill virally infected or malignant cells. Natural killer cell deficiency (NKD) occurs when NK cell development or function are impaired, and individuals with NKD are susceptible to severe and recurrent viral infections. Several gene deficiencies result in NKD, including variants in MCM4, GINS1, MCM10 and GINS4, which are components of the CDC45-MCM-GINS (CMG) helicase. The CMG helicase unwinds DNA during replication and is expressed in any actively proliferating cell. NK cells are more strongly impacted by mutational deficiencies in helicase proteins than other lymphocytes, though the mechanisms underlying this susceptibility are not completely understood. NK cells from individuals with NKD as a result of helicase deficiency have increased DNA damage, cell cycle arrest, and replication stress. Here, we induced replication stress in activated mature NK cells or T cells by chemical methods, using aphidicolin, and through shRNA knockdown of MCM10 in an NK cell line. We found that the CD56bright subset of NK cells accumulates more DNA damage and replication stress during activation than CD56dim NK cells or activated T cells. Aphidicolin treatment increases apoptosis of CD56bright NK cells through increased pan-caspase expression and decreases perforin expression in surviving cells. This effect is modeled by shRNA mediated knockdown of MCM10, thus linking decreased helicase protein expression to replication stress and impaired NK cell function. These findings show that sensitivity to replication stress affects human NK cell survival and function and can contribute to NK cell deficiency.

immunology↗

bioRxiv2018

The CD56bright CD62L+ NKG2A+ immature cell subset is dominantly expanded in human cytokine-induced memory-like NK cells

Recent studies have revealed immunological memory of NK cells. Short-term in vitro cytokine stimulation also induces NK cell memory, but heterogeneous cell subsets within the cytokine-induced memory-like (CIML) NK cells has not been elucidated. Here we found that the dominant cell subset in human CIML NK cells are immature CD56bright CD62L+cells, and they were selectively expanded CD56bright CD16- CD62L+ NK cells. Although these cells acquired KIR expression after the cytokine stimulation, sustained NKG2A expression inhibits cytotoxicity against HLA-E+ target cells. In contrast, another checkpoint molecule LAG-3 is induced mainly on KIR+ NKG2C+ minor CIML NK cells. Our findings imply targeting NKG2A and LAG-3 should be considered for CIML NK cell-based immunotherapy.

immunology↗