Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency
Julien Cottineau, … , Agata Smogorzewska, Emmanuelle Jouanguy
Julien Cottineau, … , Agata Smogorzewska, Emmanuelle Jouanguy
Published April 17, 2017
Citation Information: J Clin Invest. 2017;127(5):1991-2006. https://doi.org/10.1172/JCI90727.
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Research Article Immunology

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.

Authors

Julien Cottineau, Molly C. Kottemann, Francis P. Lach, Young-Hoon Kang, Frédéric Vély, Elissa K. Deenick, Tomi Lazarov, Laure Gineau, Yi Wang, Andrea Farina, Marie Chansel, Lazaro Lorenzo, Christelle Piperoglou, Cindy S. Ma, Patrick Nitschke, Aziz Belkadi, Yuval Itan, Bertrand Boisson, Fabienne Jabot-Hanin, Capucine Picard, Jacinta Bustamante, Céline Eidenschenk, Soraya Boucherit, Nathalie Aladjidi, Didier Lacombe, Pascal Barat, Waseem Qasim, Jane A. Hurst, Andrew J. Pollard, Holm H. Uhlig, Claire Fieschi, Jean Michon, Vladimir P. Bermudez, Laurent Abel, Jean-Pierre de Villartay, Frédéric Geissmann, Stuart G. Tangye, Jerard Hurwitz, Eric Vivier, Jean-Laurent Casanova, Agata Smogorzewska, Emmanuelle Jouanguy

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Figure 2

Identification of GINS1 mutations.

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Identification of GINS1 mutations. (A) Pedigrees of the 4 families, show...
(A) Pedigrees of the 4 families, showing allele segregation. The index case is indicated by an arrow, and “E?” indicates an unknown genotype. The age of each patient is indicated in parentheses. (B) Schematic diagram of the structure of the GINS1 cDNA, consisting of 7 exons, indicating the positions of mutations. The arrows show the primers used for cDNA amplification. Electrophoresis of PCR products from GINS1 cDNA for a control (C+), P2, P2’s father (F), P2’s mother (M), P3, P4, and P5. Ex1, exon 1. (C) Schematic diagram of the relative expression levels of each allele corresponding to the various genotypes as assessed by cloning of the cDNA molecules from patient fibroblasts.