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, 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
Journal of Clinical Investigation. 2017-04-17; 127(5): 1991-2006
DOI: 10.1172/JCI90727


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1. J Clin Invest. 2017 May 1;127(5):1991-2006. doi: 10.1172/JCI90727. Epub 2017 Apr
17.

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

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.

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.

DOI: 10.1172/JCI90727
PMCID: PMC5409070
PMID: 28414293 [Indexed for MEDLINE]

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