{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T12:14:06Z","timestamp":1783685646201,"version":"3.55.0"},"reference-count":24,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2022,7,1]],"date-time":"2022-07-01T00:00:00Z","timestamp":1656633600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["270949263\/GRK2162"],"award-info":[{"award-number":["270949263\/GRK2162"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["SA 4171\/1\u20101"],"award-info":[{"award-number":["SA 4171\/1\u20101"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001655","name":"Deutscher Akademischer Austauschdienst","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001655","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001695","name":"Japan Science and Technology Corporation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001695","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["19K22518"],"award-info":[{"award-number":["19K22518"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["19K07393"],"award-info":[{"award-number":["19K07393"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["1K06828"],"award-info":[{"award-number":["1K06828"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["1H02699"],"award-info":[{"award-number":["1H02699"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["20H03452"],"award-info":[{"award-number":["20H03452"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP21K06531"],"award-info":[{"award-number":["JP21K06531"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100013143","name":"Manton Center for Orphan Disease Research, Boston Children's Hospital","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100013143","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science and Technology","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["1K08NS123552\u201001"],"award-info":[{"award-number":["1K08NS123552\u201001"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100017026","name":"Spastic Paraplegia Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100017026","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004350","name":"Studienstiftung des Deutschen Volkes","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004350","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007449","name":"Takeda Science Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007449","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001655","name":"Deutscher Akademischer Austauschdienst","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001655","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004350","name":"Studienstiftung des Deutschen Volkes","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004350","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2022,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Childhood\u2010onset forms of hereditary spastic paraplegia are ultra\u2010rare diseases and often present with complex features. Next\u2010generation\u2010sequencing allows for an accurate diagnosis in many cases but the interpretation of novel variants remains challenging, particularly for missense mutations. Where sufficient knowledge of the protein function and\/or downstream pathways exists, functional studies in patient\u2010derived cells can aid the interpretation of molecular findings. We here illustrate the case of a 13\u2010year\u2010old female who presented with global developmental delay and later mild intellectual disability, progressive spastic diplegia, spastic\u2010ataxic gait, dysarthria, urinary urgency, and loss of deep tendon reflexes of the lower extremities. Exome sequencing showed a novel splice\u2010site variant <jats:italic>in trans<\/jats:italic> with a novel missense variant in <jats:italic>B4GALNT1<\/jats:italic> [NM_001478.5: c.532\u20101G&gt;C\/c.1556G&gt;C (p.Arg519Pro)]. Functional studies in patient\u2010derived fibroblasts and cell models of GM2 synthase deficiency confirmed a loss of B4GALNT1 function with no synthesis of GM2 and other downstream gangliosides. Collectively these results established the diagnosis of <jats:italic>B4GALNT1<\/jats:italic>\u2010associated HSP (SPG26). Our approach illustrates the importance of careful phenotyping and functional characterization of novel gene variants, particularly in the setting of ultra\u2010rare diseases, and expands the clinical and molecular spectrum of SPG26, a disorder of complex ganglioside biosynthesis.<\/jats:p>","DOI":"10.1002\/ajmg.a.62880","type":"journal-article","created":{"date-parts":[[2022,7,1]],"date-time":"2022-07-01T10:56:45Z","timestamp":1656673005000},"page":"2590-2598","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Functional validation of novel variants in <scp><i>B4GALNT1<\/i><\/scp> associated with early\u2010onset complex hereditary spastic paraplegia with impaired ganglioside synthesis"],"prefix":"10.1002","volume":"188","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1420-9775","authenticated-orcid":false,"given":"Julian Emanuel","family":"Alecu","sequence":"first","affiliation":[{"name":"Department of Neurology and F.M. Kirby Neurobiology Center Boston Children's Hospital, Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhsuke","family":"Ohmi","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences Chubu University College of Life and Health Sciences  Kasugai Japan"},{"name":"Department of Medical Technology Chubu University College of Life and Health Sciences  Kasugai Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robiul H.","family":"Bhuiyan","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences Chubu University College of Life and Health Sciences  Kasugai Japan"},{"name":"Department of Biochemistry and Molecular Biology University of Chittagong Faculty of Biological Sciences  Chittagong Bangladesh"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kei\u2010ichiro","family":"Inamori","sequence":"additional","affiliation":[{"name":"Division of Glycopathology, Institute of Molecular Biomembrane and Glycobiology Tohoku Medical and Pharmaceutical University  Sendai Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takahiro","family":"Nitta","sequence":"additional","affiliation":[{"name":"Division of Glycopathology, Institute of Molecular Biomembrane and Glycobiology Tohoku Medical and Pharmaceutical University  Sendai Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Afshin","family":"Saffari","sequence":"additional","affiliation":[{"name":"Department of Neurology and F.M. Kirby Neurobiology Center Boston Children's Hospital, Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hellen","family":"Jumo","sequence":"additional","affiliation":[{"name":"Department of Neurology and F.M. Kirby Neurobiology Center Boston Children's Hospital, Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marvin","family":"Ziegler","sequence":"additional","affiliation":[{"name":"Department of Neurology and F.M. Kirby Neurobiology Center Boston Children's Hospital, Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudio Melo","family":"de Gusmao","sequence":"additional","affiliation":[{"name":"Department of Neurology and F.M. Kirby Neurobiology Center Boston Children's Hospital, Harvard Medical School  Boston Massachusetts USA"},{"name":"Movement Disorders Program, Department of Neurology Boston Children's Hospital, Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nutan","family":"Sharma","sequence":"additional","affiliation":[{"name":"Movement Disorders Unit, Department of Neurology Massachusetts General Hospital, Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiho","family":"Ohno","sequence":"additional","affiliation":[{"name":"Division of Structural Glycobiology, Institute of Molecular Biomembrane and Glycobiology Tohoku Medical and Pharmaceutical University  Sendai Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noriyoshi","family":"Manabe","sequence":"additional","affiliation":[{"name":"Division of Structural Glycobiology, Institute of Molecular Biomembrane and Glycobiology Tohoku Medical and Pharmaceutical University  Sendai Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiki","family":"Yamaguchi","sequence":"additional","affiliation":[{"name":"Division of Structural Glycobiology, Institute of Molecular Biomembrane and Glycobiology Tohoku Medical and Pharmaceutical University  Sendai Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariko","family":"Kambe","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences Chubu University College of Life and Health Sciences  Kasugai Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keiko","family":"Furukawa","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences Chubu University College of Life and Health Sciences  Kasugai Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mustafa","family":"Sahin","sequence":"additional","affiliation":[{"name":"Department of Neurology and F.M. Kirby Neurobiology Center Boston Children's Hospital, Harvard Medical School  Boston Massachusetts USA"},{"name":"Rosamund Stone Zander Translational Neuroscience Center Boston Children's Hospital, Harvard Medical School  Boston Massachusetts USA"},{"name":"Intellectual and Developmental Disabilities Research Center Boston Children's Hospital  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin\u2010ichi","family":"Inokuchi","sequence":"additional","affiliation":[{"name":"Division of Glycopathology, Institute of Molecular Biomembrane and Glycobiology Tohoku Medical and Pharmaceutical University  Sendai Japan"},{"name":"Core for Medicine and Science Collaborative Research and Education (MS\u2010CORE), Project Research Center for Fundamental Sciences Osaka University  Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koichi","family":"Furakawa","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences Chubu University College of Life and Health Sciences  Kasugai Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0026-4714","authenticated-orcid":false,"given":"Darius","family":"Ebrahimi\u2010Fakhari","sequence":"additional","affiliation":[{"name":"Department of Neurology and F.M. Kirby Neurobiology Center Boston Children's Hospital, Harvard Medical School  Boston Massachusetts USA"},{"name":"Movement Disorders Program, Department of Neurology Boston Children's Hospital, Harvard Medical School  Boston Massachusetts USA"},{"name":"Intellectual and Developmental Disabilities Research Center Boston Children's Hospital  Boston Massachusetts USA"},{"name":"The Manton Center for Orphan Disease Research Boston Children's Hospital  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,7]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddz310"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2018.11.034"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/b978-0-444-64076-5.00041-7"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2013.05.006"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1006\/exnr.2000.7504"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1212\/NXG.0000000000000156"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/braincomms\/fcab221"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.34.20836"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0304-4165(02)00403-8"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M116.771253"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awt270"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03819-2"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bty897"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.24206"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0206881"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky1016"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2015.03.007"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.13.7532"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1460"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btz482"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.20.10662"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.12312"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2021.02.004"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2004.020172"}],"container-title":["American Journal of Medical Genetics Part A"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ajmg.a.62880","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ajmg.a.62880","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ajmg.a.62880","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,22]],"date-time":"2023-08-22T05:14:26Z","timestamp":1692681266000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ajmg.a.62880"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7]]},"references-count":24,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2022,9]]}},"alternative-id":["10.1002\/ajmg.a.62880"],"URL":"https:\/\/doi.org\/10.1002\/ajmg.a.62880","archive":["Portico"],"relation":{},"ISSN":["1552-4825","1552-4833"],"issn-type":[{"value":"1552-4825","type":"print"},{"value":"1552-4833","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7]]},"assertion":[{"value":"2022-01-21","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-05-22","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-07-01","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}