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 language | English |
|---|---|
| Pages (from-to) | 1991-2006 |
| Number of pages | 16 |
| Journal | Journal of Clinical Investigation |
| Volume | 127 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - 1 May 2017 |
| Externally published | Yes |
Fingerprint
ASJC Scopus subject areas
- Medicine(all)
Cite this
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 journal › Article
}
TY - JOUR
T1 - Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency
AU - Cottineau, Julien
AU - Kottemann, Molly C.
AU - Lach, Francis P.
AU - Kang, Young Hoon
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
AU - Casanova, Jean Laurent
AU - Smogorzewska, Agata
AU - Jouanguy, Emmanuelle
PY - 2017/5/1
Y1 - 2017/5/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85018993845&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85018993845&partnerID=8YFLogxK
U2 - 10.1172/JCI90727
DO - 10.1172/JCI90727
M3 - Article
VL - 127
SP - 1991
EP - 2006
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 5
ER -