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

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, Abdelaziz Belkadi, Yuval Itan, Bertrand Boisson, Fabienne Jabot-Hanin, Capucine PicardJacinta 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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25 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1991-2006
Number of pages16
JournalJournal of Clinical Investigation
Volume127
Issue number5
DOIs
Publication statusPublished - 1 May 2017
Externally publishedYes

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Neutropenia
Natural Killer Cells
DNA Replication
Growth
Phenotype
Bone Marrow
Lethal Genes
Gene Components
Mutation
Fetal Growth Retardation
Genomic Instability
Cell Cycle Checkpoints
DNA Repair
Fibroblasts
Genotype

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Cottineau, J., Kottemann, M. C., Lach, F. P., Kang, Y. H., Vély, F., Deenick, E. K., ... Jouanguy, E. (2017). Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency. Journal of Clinical Investigation, 127(5), 1991-2006. https://doi.org/10.1172/JCI90727

Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency. / 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, Abdelaziz; 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.

In: Journal of Clinical Investigation, Vol. 127, No. 5, 01.05.2017, p. 1991-2006.

Research output: Contribution to journalArticle

Cottineau, J, Kottemann, MC, Lach, FP, Kang, YH, Vély, F, Deenick, EK, Lazarov, T, Gineau, L, Wang, Y, Farina, A, Chansel, M, Lorenzo, L, Piperoglou, C, Ma, CS, Nitschke, P, Belkadi, A, Itan, Y, Boisson, B, Jabot-Hanin, F, Picard, C, Bustamante, J, Eidenschenk, C, Boucherit, S, Aladjidi, N, Lacombe, D, Barat, P, Qasim, W, Hurst, JA, Pollard, AJ, Uhlig, HH, Fieschi, C, Michon, J, Bermudez, VP, Abel, L, De Villartay, JP, Geissmann, F, Tangye, SG, Hurwitz, J, Vivier, E, Casanova, JL, Smogorzewska, A & Jouanguy, E 2017, 'Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency', Journal of Clinical Investigation, vol. 127, no. 5, pp. 1991-2006. https://doi.org/10.1172/JCI90727
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, Abdelaziz ; 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. / Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency. In: Journal of Clinical Investigation. 2017 ; Vol. 127, No. 5. pp. 1991-2006.
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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.",
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AU - Vély, Frédéric

AU - Deenick, Elissa K.

AU - Lazarov, Tomi

AU - Gineau, Laure

AU - Wang, Yi

AU - Farina, Andrea

AU - Chansel, Marie

AU - Lorenzo, Lazaro

AU - Piperoglou, Christelle

AU - Ma, Cindy S.

AU - Nitschke, Patrick

AU - Belkadi, Abdelaziz

AU - Itan, Yuval

AU - Boisson, Bertrand

AU - Jabot-Hanin, Fabienne

AU - Picard, Capucine

AU - Bustamante, Jacinta

AU - Eidenschenk, Céline

AU - Boucherit, Soraya

AU - Aladjidi, Nathalie

AU - Lacombe, Didier

AU - Barat, Pascal

AU - Qasim, Waseem

AU - Hurst, Jane A.

AU - Pollard, Andrew J.

AU - Uhlig, Holm H.

AU - Fieschi, Claire

AU - Michon, Jean

AU - Bermudez, Vladimir P.

AU - Abel, Laurent

AU - De Villartay, Jean Pierre

AU - Geissmann, Frédéric

AU - Tangye, Stuart G.

AU - Hurwitz, Jerard

AU - Vivier, Eric

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