{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T23:17:16Z","timestamp":1789514236965,"version":"build-2803163510"},"reference-count":74,"publisher":"American Society for Clinical Investigation","issue":"21","license":[{"start":{"date-parts":[[2022,11,8]],"date-time":"2022-11-08T00:00:00Z","timestamp":1667865600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["NIH-AI120989"],"award-info":[{"award-number":["NIH-AI120989"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,11,8]]},"abstract":"<jats:p>\n                    Human NK cell deficiency (NKD) is a primary immunodeficiency in which the main clinically relevant immunological defect involves missing or dysfunctional NK cells. Here, we describe a familial NKD case in which 2 siblings had a substantive NKD and neutropenia in the absence of other immune system abnormalities. Exome sequencing identified compound heterozygous variants in Go-Ichi-Ni-San (GINS) complex subunit 4 (\n                    <jats:italic>GINS4<\/jats:italic>\n                    , also known as\n                    <jats:italic>SLD5<\/jats:italic>\n                    ), an essential component of the human replicative helicase, which we demonstrate to have a damaging impact upon the expression and assembly of the GINS complex. Cells derived from affected individuals and a\n                    <jats:italic>GINS4<\/jats:italic>\n                    -knockdown cell line demonstrate delayed cell cycle progression, without signs of improper DNA synthesis or increased replication stress. By modeling partial\n                    <jats:italic>GINS4<\/jats:italic>\n                    depletion in differentiating NK cells in vitro, we demonstrate the causal relationship between the genotype and the NK cell phenotype, as well as a cell-intrinsic defect in NK cell development. Thus, biallelic partial loss-of-function mutations in\n                    <jats:italic>GINS4<\/jats:italic>\n                    define a potentially novel disease-causing gene underlying NKD with neutropenia. Together with the previously described mutations in other helicase genes causing NKD, and with the mild defects observed in other human cells, these variants underscore the importance of this pathway in NK cell biology.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.154948","type":"journal-article","created":{"date-parts":[[2022,11,7]],"date-time":"2022-11-07T14:01:03Z","timestamp":1667829663000},"source":"Crossref","is-referenced-by-count":26,"title":["Partial loss-of-function mutations in GINS4 lead to NK cell deficiency with neutropenia"],"prefix":"10.1172","volume":"7","author":[{"given":"Matilde I.","family":"Conte","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6817-0573","authenticated-orcid":true,"given":"M. Cecilia","family":"Poli","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Cl\u00ednica Alemana Universidad del Desarrollo, Santiago, Chile."},{"name":"Immunology and Rheumatology Unit, Hospital Roberto del Rio, Santiago, Chile."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelo","family":"Taglialatela","sequence":"additional","affiliation":[{"name":"Department of Genetics and Development, Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2211-790X","authenticated-orcid":true,"given":"Giuseppe","family":"Leuzzi","sequence":"additional","affiliation":[{"name":"Department of Genetics and Development, Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York, 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