{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T19:34:05Z","timestamp":1768505645654,"version":"3.49.0"},"posted":{"date-parts":[[2023,1,8]]},"group-title":"Cell Biology","reference-count":55,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,1,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Hereditary spastic paraplegia (HSP) is a group of degenerative neurological disorders. We identified a variant in human kinesin light chain\n                  <jats:italic>KLC4<\/jats:italic>\n                  that is suspected to be associated with autosomal dominant HSP. How this and other variants relate to pathologies is unknown. We created a humanized\n                  <jats:italic>C. elegans<\/jats:italic>\n                  model where\n                  <jats:italic>klc-<\/jats:italic>\n                  2 was replaced with human\n                  <jats:italic>KLC4<\/jats:italic>\n                  and assessed the extent to which\n                  <jats:italic>hKLC4<\/jats:italic>\n                  retained function in the worm. We observed a slight decrease in motility but no nuclear migration defects in the humanized worms, suggesting that\n                  <jats:italic>hKLC4<\/jats:italic>\n                  retains much of the function of\n                  <jats:italic>klc-2<\/jats:italic>\n                  . Five\n                  <jats:italic>hKLC4<\/jats:italic>\n                  variants were introduced into the humanized model. The clinical variant led to early lethality with significant defects in nuclear migration when homozygous, and a weak nuclear migration defect when heterozygous, possibly correlating with the clinical finding of late onset HSP when the proband was heterozygous. Thus, we were able to establish humanized\n                  <jats:italic>C. elegans<\/jats:italic>\n                  as an animal model for HSP and use it to test the significance of five variants of uncertain significance in the human gene\n                  <jats:italic>KLC4<\/jats:italic>\n                  .\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Summary Statement<\/jats:title>\n                  <jats:p>\n                    We identified a variant in\n                    <jats:italic>KLC4<\/jats:italic>\n                    associated with Hereditary Spastic Paraplegia. The variant had physiological relevance in a humanized\n                    <jats:italic>C. elegans<\/jats:italic>\n                    model where we replaced\n                    <jats:italic>klc-2<\/jats:italic>\n                    with human\n                    <jats:italic>KLC4<\/jats:italic>\n                    .\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2023.01.07.523106","type":"posted-content","created":{"date-parts":[[2023,1,8]],"date-time":"2023-01-08T11:45:12Z","timestamp":1673178312000},"source":"Crossref","is-referenced-by-count":2,"title":["A humanized\n                  <i>Caenorhabditis elegans<\/i>\n                  model of Hereditary Spastic Paraplegia-associated variants in kinesin light chain KLC4"],"prefix":"10.64898","author":[{"given":"Selin","family":"G\u00fcm\u00fc\u015fderelio\u011flu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lauren","family":"Resch","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Trisha","family":"Brock","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"Undiagnosed Diseases Network","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6180-8906","authenticated-orcid":false,"given":"G.W. 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