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

Julien Cottineau (1, 2, 3) , Molly C. Kottemann , Francis P. Lach , Young-Hoon Kang , Frederic Vely (4, 5) , Elissa K. Deenick , Tomi Lazarov , Laure Gineau (1, 2, 3) , Yi Wang (6, 1, 2, 3) , Andrea Farina (7) , Marie Chansel (2, 3) , Lazaro Lorenzo (1, 2, 3) , Christelle Piperoglou (8, 5) , Cindy S. Ma (9, 10) , Patrick Nitschke (3, 2, 1) , Aziz Belkadi (3, 1, 2) , Yuval Itan (11) , Bertrand Boisson (3, 12, 1, 2) , Fabienne Jabot-Hanin (1, 2) , Capucine Picard (13, 1, 2, 3) , Jacinta Bustamante (3, 1, 2) , Celine Eidenschenk (1, 2, 3) , Soraya Boucherit (1, 2, 3) , Nathalie Aladjidi (14, 15) , Didier Lacombe (16) , Pascal Barat (17, 18, 19, 20) , Waseem Qasim (21) , Jane A. Hurst , Andrew J. Pollard (22) , Holm H. Uhlig , Claire Fieschi (23) , Jean Michon (24, 25) , Vladimir P. Bermudez , Laurent Abel (3, 11, 1, 2) , Jean-Pierre De Villartay (2, 3) , Frederic Geissmann (26) , Stuart G. Tangye (9, 10) , Jerard Hurwitz , Eric Vivier (5) , Jean-Laurent Casanova (1, 3, 11, 27, 2) , Agata Smogorzewska (28) , Emmanuelle Jouanguy (1, 2, 3)

1 CHU Necker - Enfants Malades [AP-HP]
2 UPD5 - Université Paris Descartes - Paris 5
3 IMAGINE - U1163 - Imagine - Institut des maladies génétiques
4 Service d'Immunologie [AP-HM]
5 CIML - Centre d'Immunologie de Marseille - Luminy
6 JHU - Johns Hopkins University
7 IFN - CNR Istituto di Fotonica e Nanotecnologie [Milano]
8 Laboratoire d'Immunologie [Hôpital de la Conception - APHM]
9 Immunology Program
10 St. Vincent’s Clinical School, Faculty of Medicine
11 St. Giles Laboratory of Human Genetics of Infectious Diseases
12 Rockefeller University [New York]
13 Plateforme de génomique [SFR Necker]
14 Service d'Hémato-oncologie Pédiatrique
15 CIC - Bordeaux
16 Service de génétique médicale
17 NutriNeuro - Nutrition et Neurobiologie intégrée
18 Centre de Recherche Cardio-thoracique de Bordeaux, U1045
19 UB - Université de Bordeaux
20 CIC 1401 - Centre d’Investigation Clinique de Bordeaux
21 GOSH - Great Ormond Street Hospital for Children [London]
22 Univ Oxford, NIHR Oxford Biomed Res Ctr, Childrens Hosp, Dept Paediat
23 Service d'immunologie clinique
24 SFCE - Société française de lutte contre les cancers et les leucémies de l’enfant et de l’adolescent
25 CHU Trousseau [APHP]
26 Memorial Sloane Kettering Cancer Center [New York]
27 HHMI - Howard Hughes Medical Institute
28 The rockefeller university - LABORATORY OF GENOME MAINTENANCE

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.

Keywords: NK cell deficiency; Neutropenia

Domains: Life Sciences [q-bio]; Immunology

Julien Cottineau, Molly C. Kottemann, Francis P. Lach, Young-Hoon Kang, Frederic Vely, et al.. Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency. Journal of Clinical Investigation, 2017, 127 (5), pp.1991-2006. ⟨10.1172/JCI90727⟩. ⟨hal-01765083⟩