{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T20:52:56Z","timestamp":1784580776460,"version":"3.55.0"},"reference-count":20,"publisher":"BMJ","issue":"2","funder":[{"name":"National Institute of Neurological Disorders and Stroke of the National Institutes of Health","award":["1U01HG010230"],"award-info":[{"award-number":["1U01HG010230"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2024,11,3]]},"published-print":{"date-parts":[[2025,2]]},"abstract":"<jats:p>\n                  <jats:italic>KIF21A<\/jats:italic> encodes a kinesin motor protein associated with isolated congenital fibrosis of the extraocular muscles (CFEOM), which occurs when the autoinhibitory interaction between its motor and third coiled-coil domains is disrupted. In this study, we describe a female child who is heterozygous for a novel de novo missense variant in <jats:italic>KIF21A<\/jats:italic> p.Leu664Pro, located in the second coiled-coil domain that was absent in her unaffected parents and in healthy population cohorts. She presented with progressive peripheral neuropathy, hypoplasia of the corpus callosum and strabismus in the absence of CFEOM. Protein modelling predicts that the KIF21A variant leads to significant alterations in its structure as well as binding with TUBB3. Co-immunoprecipitation data was consistent with decreased binding of KIF21A p.Leu664Pro to TUBB3 in vitro compared with reference. Taken together, we delineate a <jats:italic>KIF21A<\/jats:italic>-related phenotype defined by progressive peripheral neuropathy, brain anomalies, developmental delay and comitant strabismus potentially stemming from the disruption of the interaction between KIF21A and TUBB3.<\/jats:p>","DOI":"10.1136\/jmg-2024-109908","type":"journal-article","created":{"date-parts":[[2024,12,6]],"date-time":"2024-12-06T13:20:30Z","timestamp":1733491230000},"page":"117-122","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":3,"title":["<i>KIF21A<\/i>-associated peripheral neuropathy defined by impaired binding with TUBB3"],"prefix":"10.1136","volume":"62","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9199-9096","authenticated-orcid":false,"given":"Nicholas A","family":"Borja","sequence":"first","affiliation":[{"name":"Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, Florida, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad Faraz","family":"Zafeer","sequence":"additional","affiliation":[{"name":"John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Bivona","sequence":"additional","affiliation":[{"name":"Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, Florida, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L\u00e9Shon","family":"Peart","sequence":"additional","affiliation":[{"name":"John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sakir Humayun","family":"Gultekin","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Miami Miller School of Medicine, Miami, Florida, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Undiagnosed Diseases Network","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guney","family":"Bademci","sequence":"additional","affiliation":[{"name":"Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, Florida, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mustafa","family":"Tekin","sequence":"additional","affiliation":[{"name":"Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, Florida, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2024,12,6]]},"reference":[{"key":"2025100520194584000_62.2.117.1","doi-asserted-by":"crossref","DOI":"10.3389\/fnins.2023.1226181","article-title":"TUBB3 and KIF21A in neurodevelopment and disease","volume":"17","author":"Puri","year":"2023","journal-title":"Front Neurosci"},{"key":"2025100520194584000_62.2.117.2","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1172\/JCI168554","article-title":"Disruption of axonal transport in neurodegeneration","volume":"133","author":"Berth","year":"2023","journal-title":"J Clin Invest"},{"key":"2025100520194584000_62.2.117.3","doi-asserted-by":"publisher","DOI":"10.1038\/ng1261"},{"key":"2025100520194584000_62.2.117.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2009.12.011"},{"key":"2025100520194584000_62.2.117.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.gde.2011.01.003"},{"key":"2025100520194584000_62.2.117.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.07.029"},{"key":"2025100520194584000_62.2.117.7","doi-asserted-by":"crossref","DOI":"10.1038\/srep30668","article-title":"Structural basis for misregulation of kinesin KIF21A autoinhibition by CFEOM1 disease mutations","volume":"6","author":"Bianchi","year":"2016","journal-title":"Sci Rep"},{"key":"2025100520194584000_62.2.117.8","first-page":"368","article-title":"A novel de novo KIF21A mutation in a patient with congenital fibrosis of the extraocular muscles and M\u00f6bius syndrome","volume":"20","author":"Ali","year":"2014","journal-title":"Mol Vis"},{"key":"2025100520194584000_62.2.117.9","doi-asserted-by":"crossref","DOI":"10.1002\/ajmg.a.63455","article-title":"Phenotypic heterogeneity associated with KIF21A: Two new cases and review of the literature","volume":"194","author":"Bhola","year":"2024","journal-title":"Am J Med Genet A"},{"key":"2025100520194584000_62.2.117.10","doi-asserted-by":"crossref","DOI":"10.1186\/s13023-022-02582-5","article-title":"Clinical and genetic characteristics of Chinese patients with congenital cranial dysinnervation disorders","volume":"17","author":"Jia","year":"2022","journal-title":"Orphanet J Rare Dis"},{"key":"2025100520194584000_62.2.117.11","doi-asserted-by":"publisher","DOI":"10.1097\/WNO.0000000000000921"},{"key":"2025100520194584000_62.2.117.12","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2021-108064"},{"key":"2025100520194584000_62.2.117.13","doi-asserted-by":"publisher","DOI":"10.1038\/ng.806"},{"key":"2025100520194584000_62.2.117.14","doi-asserted-by":"publisher","DOI":"10.1093\/NAR\/GKAD1011"},{"key":"2025100520194584000_62.2.117.15","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2308-7"},{"key":"2025100520194584000_62.2.117.16","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2016.08.016"},{"key":"2025100520194584000_62.2.117.17","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2890"},{"key":"2025100520194584000_62.2.117.18","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"2025100520194584000_62.2.117.19","doi-asserted-by":"crossref","DOI":"10.1126\/science.adg7492","article-title":"Accurate proteome-wide missense variant effect prediction with AlphaMissense","volume":"381","author":"Cheng","year":"2023","journal-title":"Science"},{"key":"2025100520194584000_62.2.117.20","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-023-39306-7","article-title":"Deep structured learning for variant prioritization in Mendelian diseases","volume":"14","author":"Danzi","year":"2023","journal-title":"Nat Commun"}],"container-title":["Journal of Medical Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jmg-2024-109908","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T03:19:56Z","timestamp":1759720796000},"score":1,"resource":{"primary":{"URL":"https:\/\/jmg.bmj.com\/lookup\/doi\/10.1136\/jmg-2024-109908"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,6]]},"references-count":20,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2025,1,27]]},"published-print":{"date-parts":[[2025,2]]}},"alternative-id":["10.1136\/jmg-2024-109908"],"URL":"https:\/\/doi.org\/10.1136\/jmg-2024-109908","relation":{},"ISSN":["0022-2593","1468-6244"],"issn-type":[{"value":"0022-2593","type":"print"},{"value":"1468-6244","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,6]]}}}