{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T03:49:31Z","timestamp":1761709771562,"version":"3.37.3"},"reference-count":33,"publisher":"Oxford University Press (OUP)","issue":"20","license":[{"start":{"date-parts":[[2020,10,15]],"date-time":"2020-10-15T00:00:00Z","timestamp":1602720000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"KU Leuven BOF","award":["C14\/19\/096"],"award-info":[{"award-number":["C14\/19\/096"]}]},{"DOI":"10.13039\/501100012112","name":"Swedish Orphan Biovitrum","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100012112","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,12,18]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>We describe a lethal combined nervous and reproductive systems disease in three affected siblings of a consanguineous family. The phenotype was characterized by visceroautonomic dysfunction (neonatal bradycardia\/apnea, feeding problems, hyperactive startle reflex), severe postnatal progressive neurological abnormalities (including abnormal neonatal cry, hypotonia, epilepsy, polyneuropathy, cerebral gray matter atrophy), visual impairment, testicular dysgenesis in males and sudden death at infant age by brainstem-mediated cardiorespiratory arrest. Whole-exome sequencing revealed a novel homozygous frameshift variant p.Val242GlufsTer52 in the TSPY-like 1 gene (TSPYL1). The truncated TSPYL1 protein that lacks the nucleosome assembly protein domain was retained in the Golgi of fibroblasts from the three patients, whereas control fibroblasts express full-length TSPYL1 in the nucleus. Proteomic analysis of nuclear extracts from fibroblasts identified 24 upregulated and 20 downregulated proteins in the patients compared with 5 controls with \u2018regulation of cell cycle\u2019 as the highest scored biological pathway affected. TSPYL1-deficient cells had prolonged S and G2 phases with reduced cellular proliferation rates. Tspyl1 depletion in zebrafish mimicked the patients\u2019 phenotype with early lethality, defects in neurogenesis and cardiac dilation. In conclusion, this study reports the third pedigree with recessive TSPYL1 variants, confirming that TSPYL1 deficiency leads to a combined nervous and reproductive systems disease, and provides for the first time insights into the disease mechanism.<\/jats:p>","DOI":"10.1093\/hmg\/ddaa233","type":"journal-article","created":{"date-parts":[[2020,10,14]],"date-time":"2020-10-14T19:12:24Z","timestamp":1602702744000},"page":"3431-3442","source":"Crossref","is-referenced-by-count":4,"title":["Unravelling the disease mechanism for TSPYL1 deficiency"],"prefix":"10.1093","volume":"29","author":[{"given":"Gunnar","family":"Buyse","sequence":"first","affiliation":[{"name":"Department of Pediatric Neurology, University Hospitals Leuven, 3000 Leuven, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michela","family":"Di Michele","sequence":"additional","affiliation":[{"name":"Institut des Biomol\u00e9cules Max Mousseron (IBMM), UMR 5247, Universit\u00e9 de Montpellier, Ecole Nationale Sup\u00e9rieure de Chimie de Montpellier, 34090 Montpellier, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anouck","family":"Wijgaerts","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, Leuven 3000, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sophie","family":"Louwette","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, Leuven 3000, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christine","family":"Wittevrongel","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, Leuven 3000, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chantal","family":"Thys","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, Leuven 3000, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kate","family":"Downes","sequence":"additional","affiliation":[{"name":"East Genomic Laboratory Hub, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK"},{"name":"Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Berten","family":"Ceulemans","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology, University hospital, University of Antwerp, 2000 Antwerp, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hild","family":"Van Esch","sequence":"additional","affiliation":[{"name":"Center for Human Genetics, University Hospitals Leuven, 3000 Leuven, Belgium"},{"name":"Laboratory for the Genetics of Cognition, Department of Human Genetics, KU Leuven, 3000 Leuven, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chris","family":"Van Geet","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology, University Hospitals Leuven, 3000 Leuven, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kathleen","family":"Freson","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, Leuven 3000, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2020,10,19]]},"reference":[{"key":"2020121910194265700_ref1","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1159\/000015042","article-title":"Murine and human TSPYL genes: novel members of the TSPY-SET-NAP1L1 family","volume":"81","author":"Vogel","year":"1998","journal-title":"Cytogenet. Cell Genet."},{"key":"2020121910194265700_ref2","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1139\/o06-088","article-title":"Structure and function of nucleosome assembly proteins","volume":"84","author":"Park","year":"2006","journal-title":"Biochem. Cell Biol."},{"key":"2020121910194265700_ref3","doi-asserted-by":"crossref","first-page":"7025","DOI":"10.1016\/S0021-9258(20)89604-5","article-title":"Identification and molecular cloning of yeast homolog of nucleosome assembly protein I which facilitates nucleosome assembly in vitro","volume":"266","author":"Ishimi","year":"1991","journal-title":"Biol. Chem."},{"key":"2020121910194265700_ref4","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1042\/bj2970389","article-title":"Molecular characterization of hNRP, a cDNA encoding a human nucleosome-assembly-protein-I-related gene product involved in the induction of cell proliferation","volume":"297","author":"Simon","year":"1994","journal-title":"Biochem. J."},{"key":"2020121910194265700_ref5","doi-asserted-by":"crossref","first-page":"15279","DOI":"10.1074\/jbc.273.24.15279","article-title":"Nucleosome assembly activity and intracellular localization of human CAF-1 changes during the cell division cycle","volume":"273","author":"Marheineke","year":"1998","journal-title":"Biol. Chem."},{"key":"2020121910194265700_ref6","doi-asserted-by":"crossref","first-page":"1014","DOI":"10.1002\/humu.23541","article-title":"De novo mutations in the SET nuclear proto-oncogene, encoding a component of the inhibitor of histone acetyltransferases (INHAT) complex in patients with nonsyndromic intellectual disability","volume":"39","author":"Stevens","year":"2018","journal-title":"Hum. Mutat."},{"key":"2020121910194265700_ref7","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1111\/j.1471-4159.2007.04747.x","article-title":"The nuclear localization of SET mediated by impalpha3\/impbeta attenuates its cytosolic toxicity in neurons","volume":"103","author":"Qu","year":"2007","journal-title":"J. Neurochem."},{"key":"2020121910194265700_ref8","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.febslet.2012.11.013","article-title":"Cytoplasmic targeting of the proto-oncogene SET promotes cell spreading and migration","volume":"587","author":"Lam","year":"2013","journal-title":"FEBS Lett."},{"key":"2020121910194265700_ref9","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1038\/s41419-019-1484-6","article-title":"Loss of SET reveals both the p53-dependent and the p53-independent functions in vivo","volume":"10","author":"Kon","year":"2019","journal-title":"Cell Death Dis."},{"key":"2020121910194265700_ref10","doi-asserted-by":"crossref","first-page":"11689","DOI":"10.1073\/pnas.0401194101","article-title":"Mapping of sudden infant death with dysgenesis of the testes syndrome (SIDDT) by a SNP genome scan and identification of TSPYL loss of function","volume":"101","author":"Puffenberger","year":"2004","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2020121910194265700_ref11","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1016\/j.fertnstert.2009.04.009","article-title":"Mutations in the TSPYL1 gene associated with 46,XY disorder of sex development and male infertility","volume":"92","author":"Vinci","year":"2009","journal-title":"Fertil. Steril."},{"key":"2020121910194265700_ref12","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1016\/j.fertnstert.2011.11.002","article-title":"Should TSPYL1 mutation screening be included in routine diagnostics of male idiopathic infertility?","volume":"97","author":"Javaher","year":"2012","journal-title":"Fertil. Steril."},{"key":"2020121910194265700_ref13","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1097\/01.gim.0000195898.15290.03","article-title":"Genetic investigation of the TSPYL1 gene in sudden infant death syndrome","volume":"8","author":"Hering","year":"2006","journal-title":"Genet. Med."},{"key":"2020121910194265700_ref14","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.mcp.2014.10.006","article-title":"Variants in TSPYL1 are not associated with sudden infant death syndrome in a cohort of deceased infants from Switzerland","volume":"29","author":"Schubert","year":"2015","journal-title":"Mol. Cell. Probes"},{"key":"2020121910194265700_ref15","doi-asserted-by":"crossref","DOI":"10.1002\/ajmg.a.61842","article-title":"Sudden infant death with dysgenesis of the testes syndrome in a non-Amish infant: a case report","author":"Slater","year":"2020","journal-title":"Am. J. Med. Genet. A"},{"key":"2020121910194265700_ref16","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1186\/s13073-015-0151-5","article-title":"Human phenotype ontology annotation and cluster analysis to unravel genetic defects in 707 cases with unexplained bleeding and platelet disorders","volume":"7","author":"Westbury","year":"2015","journal-title":"Genome Med."},{"key":"2020121910194265700_ref17","doi-asserted-by":"crossref","DOI":"10.1074\/mcp.M111.007625","article-title":"Pituitary adenylate cyclase-activating polypeptide (PACAP) impairs the regulation of apoptosis in megakaryocytes by activating NF-\u03baB: a proteomic study","volume":"11","author":"Di Michele","year":"2012","journal-title":"Mol. Cell. Proteomics"},{"key":"2020121910194265700_ref18","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1002\/dvdy.10356","article-title":"Germ-line transmission of a myocardium-specific GFP transgene reveals critical regulatory elements in the cardiac myosin light chain 2 promoter of zebrafish","volume":"228","author":"Huang","year":"2003","journal-title":"Dev. Dyn."},{"key":"2020121910194265700_ref19","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/S0896-6273(00)00034-9","article-title":"Midline signals regulate retinal neurogenesis in zebrafish","volume":"27","author":"Masai","year":"2000","journal-title":"Neuron"},{"key":"2020121910194265700_ref20","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1006\/dbio.1997.8761","article-title":"Neuronal and neuroendocrine expression of lim3, a LIM class homeobox gene, is altered in mutant zebrafish with axial signaling defects","volume":"192","author":"Glasgow","year":"1997","journal-title":"Dev. Biol."},{"key":"2020121910194265700_ref21","doi-asserted-by":"crossref","first-page":"2125","DOI":"10.1096\/fj.11-198739","article-title":"Regulator of G-protein signaling 18 controls megakaryopoiesis and the cilia-mediated vertebrate mechanosensory system","volume":"26","author":"Louwette","year":"2012","journal-title":"FASEB J."},{"key":"2020121910194265700_ref22","doi-asserted-by":"crossref","first-page":"2573","DOI":"10.1242\/dev.01831","article-title":"Staggered cell-intrinsic timing of ath5 expression underlies the wave of ganglion cell neurogenesis in the zebrafish retina","volume":"132","author":"Kay","year":"2005","journal-title":"Development"},{"key":"2020121910194265700_ref23","doi-asserted-by":"crossref","first-page":"1759","DOI":"10.1002\/stem.1702","article-title":"Knockdown of nucleosome assembly protein 1-like 1 induces mesoderm formation and cardiomyogenesis via notch signaling in murine-induced pluripotent stem cells","volume":"32","author":"Gong","year":"2014","journal-title":"Stem Cells"},{"key":"2020121910194265700_ref24","doi-asserted-by":"crossref","DOI":"10.1016\/j.gep.2019.119076","article-title":"Expression of nucleosome assembly protein 1 like genes in zebrafish embryos","volume":"35","author":"Sun","year":"2020","journal-title":"Gene Expr. Patterns"},{"key":"2020121910194265700_ref25","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/0165-0173(83)90008-5","article-title":"Functional anatomy of the tectum mesencephali of the goldfish. An explorative analysis of the functional implications of the laminar structural organization of the tectum","volume":"287","author":"Meek","year":"1983","journal-title":"Brain Res."},{"key":"2020121910194265700_ref26","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0021602","article-title":"TSPYL2 is important for G1 checkpoint maintenance upon DNA damage","volume":"6","author":"Tao","year":"2011","journal-title":"PLoS One"},{"key":"2020121910194265700_ref27","doi-asserted-by":"crossref","first-page":"1158","DOI":"10.1074\/jbc.M207497200","article-title":"The SET protein regulates G2\/M transition by modulating cyclin B-cyclin-dependent kinase 1 activity","volume":"278","author":"Canela","year":"2003","journal-title":"J. Biol. Chem."},{"key":"2020121910194265700_ref28","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1083\/jcb.130.3.661","article-title":"Members of the NAP\/SET family of proteins interact specifically with B-type cyclins","volume":"130","author":"Kellogg","year":"1995","journal-title":"J. Cell Biol."},{"key":"2020121910194265700_ref29","doi-asserted-by":"crossref","first-page":"6141","DOI":"10.1038\/onc.2008.206","article-title":"TSPY and its X-encoded homologue interact with cyclin B but exert contrasting functions on cyclin-dependent kinase 1 activities","volume":"27","author":"Li","year":"2008","journal-title":"Oncogene"},{"key":"2020121910194265700_ref30","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1177\/030098589803500601","article-title":"The cell cycle: a review","volume":"35","author":"Schafer","year":"1998","journal-title":"Vet. Pathol."},{"key":"2020121910194265700_ref31","doi-asserted-by":"crossref","first-page":"4100","DOI":"10.1091\/mbc.e02-05-0271","article-title":"Functional proteomic analysis of human nucleolus","volume":"13","author":"Scherl","year":"2002","journal-title":"Mol. Biol. Cell"},{"key":"2020121910194265700_ref32","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1111\/j.1365-2796.2010.02282.x","article-title":"Cell cycle and cell death in disease: past, present and future","volume":"268","author":"Zhivotovsky","year":"2010","journal-title":"J. Intern. Med."},{"key":"2020121910194265700_ref33","doi-asserted-by":"crossref","first-page":"2056","DOI":"10.1002\/ajmg.a.61315","article-title":"Biallelic and de novo variants in DONSON reveal a clinical Spectrum of cell cycle-opathies with microcephaly, dwarfism and skeletal abnormalities","volume":"179","author":"Karaca","year":"2019","journal-title":"Am. J. Med. Genet. A"}],"container-title":["Human Molecular Genetics"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/hmg\/advance-article-pdf\/doi\/10.1093\/hmg\/ddaa233\/34706441\/ddaa233.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/hmg\/article-pdf\/29\/20\/3431\/34950191\/ddaa233.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/hmg\/article-pdf\/29\/20\/3431\/34950191\/ddaa233.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,25]],"date-time":"2023-10-25T16:36:23Z","timestamp":1698251783000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/hmg\/article\/29\/20\/3431\/5930655"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,10,15]]},"references-count":33,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2020,10,19]]},"published-print":{"date-parts":[[2020,12,18]]}},"URL":"https:\/\/doi.org\/10.1093\/hmg\/ddaa233","relation":{},"ISSN":["0964-6906","1460-2083"],"issn-type":[{"type":"print","value":"0964-6906"},{"type":"electronic","value":"1460-2083"}],"subject":[],"published-other":{"date-parts":[[2020,10,15]]},"published":{"date-parts":[[2020,10,15]]}}}