{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T20:21:16Z","timestamp":1768508476671,"version":"3.49.0"},"posted":{"date-parts":[[2023,11,19]]},"group-title":"Genetics","reference-count":57,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,11,19]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Rare diseases are underrepresented in biomedical research, leading to insufficient awareness. Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome is a rare disease caused by genetic alterations that result in heterozygous loss-of-function of SON. While ZTTK syndrome patients suffer from numerous symptoms, the lack of model organisms hamper our understanding of both SON and this complex syndrome. Here, we developed\n                  <jats:italic>Son<\/jats:italic>\n                  haploinsufficiency (\n                  <jats:italic>\n                    Son\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                  <\/jats:italic>\n                  ) mice as a model of ZTTK syndrome and identified the indispensable roles of\n                  <jats:italic>Son<\/jats:italic>\n                  in organ development and hematopoiesis.\n                  <jats:italic>\n                    Son\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                  <\/jats:italic>\n                  mice recapitulated clinical symptoms of ZTTK syndrome, including growth retardation, cognitive impairment, skeletal abnormalities, and kidney agenesis. Furthermore, we identified hematopoietic abnormalities in\n                  <jats:italic>\n                    Son\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                  <\/jats:italic>\n                  mice, similar to those observed in human patients. Surface marker analyses and single-cell transcriptome profiling of hematopoietic stem and progenitor cells revealed that\n                  <jats:italic>Son<\/jats:italic>\n                  haploinsufficiency inclines cell fate toward the myeloid lineage but compromises lymphoid lineage development by reducing key genes required for lymphoid and B cell lineage specification. Additionally,\n                  <jats:italic>Son<\/jats:italic>\n                  haploinsufficiency causes inappropriate activation of erythroid genes and impaired erythroid maturation. These findings highlight the importance of the full gene dosage of\n                  <jats:italic>Son<\/jats:italic>\n                  in organ development and hematopoiesis. Our model serves as an invaluable research tool for this rare disease and related disorders associated with SON dysfunction.\n                <\/jats:p>","DOI":"10.1101\/2023.11.19.567732","type":"posted-content","created":{"date-parts":[[2023,11,19]],"date-time":"2023-11-19T22:05:12Z","timestamp":1700431512000},"source":"Crossref","is-referenced-by-count":1,"title":["A mouse model of ZTTK syndrome reveals indispensable SON functions in organ development and hematopoiesis"],"prefix":"10.64898","author":[{"given":"Lana","family":"Vukadin","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bohye","family":"Park","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mostafa","family":"Mohamed","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huashi","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amr","family":"Elkholy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alex","family":"Torrelli-Diljohn","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jung-Hyun","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kyuho","family":"Jeong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James M","family":"Murphy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Caitlin A.","family":"Harvey","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sophia","family":"Dunlap","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leah","family":"Gehrs","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hanna","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hyung-Gyoon","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seth N.","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Denise","family":"Stanford","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert A.","family":"Barrington","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeremy B.","family":"Foote","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna G.","family":"Sorace","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert S.","family":"Welner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"suffix":"III","given":"Blake E.","family":"Hildreth","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ssang-Taek Steve","family":"Lim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eun-Young Erin","family":"Ahn","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"issue":"2","key":"2023112208050902000_2023.11.19.567732v1.1","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1038\/s41573-019-0049-9","article-title":"Therapies for rare diseases: therapeutic modalities, progress and challenges ahead","volume":"19","year":"2020","journal-title":"Nat Rev Drug Discov"},{"issue":"2","key":"2023112208050902000_2023.11.19.567732v1.2","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1038\/d41573-019-00180-y","article-title":"How many rare diseases are there?","volume":"19","year":"2020","journal-title":"Nat Rev Drug Discov"},{"issue":"5","key":"2023112208050902000_2023.11.19.567732v1.3","doi-asserted-by":"crossref","first-page":"101123","DOI":"10.1016\/j.isci.2020.101123","article-title":"Rare Genetic Diseases: Nature\u2019s Experiments on Human Development","volume":"23","year":"2020","journal-title":"iScience"},{"key":"2023112208050902000_2023.11.19.567732v1.4","doi-asserted-by":"crossref","unstructured":"Farnaes L , Hildreth A , Sweeney NM , Clark MM , Chowdhury S , Nahas S , et al. 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