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Neurogenetics
Short report
KIF21A-associated peripheral neuropathy defined by impaired binding with TUBB3
  1. Nicholas A Borja1,
  2. Mohammad Faraz Zafeer2,
  3. Stephanie Bivona1,
  4. LéShon Peart2,
  5. Sakir Humayun Gultekin3,
  6. Undiagnosed Diseases Network4,
  7. Guney Bademci1,
  8. Mustafa Tekin1
    1. 1Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, Florida, USA
    2. 2John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, USA
    3. 3Department of Pathology, University of Miami Miller School of Medicine, Miami, Florida, USA
    4. 4National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA
    1. Correspondence to Dr Mustafa Tekin; mtekin{at}med.miami.edu

    Abstract

    KIF21A 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 KIF21A 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 KIF21A-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.

    • Human Genetics
    • Nervous System Diseases
    • Eye Diseases
    • Congenital, Hereditary, and Neonatal Diseases and Abnormalities

    https://doi.org/10.1136/jmg-2024-109908

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      Footnotes

      • Correction notice This article has been corrected since it was published online. The title has been amended.

      • Collaborators Members of the Undiagnosed Diseases Network: Maria T Acosta, David R Adams, Ben Afzali, Ali Al-Beshri, Aimee Allworth, Raquel L Alvarez, Justin Alvey, Ashley Andrews, Euan A Ashley, Carlos A Bacino, Guney Bademci, Ashok Balasubramanyam, Dustin Baldridge, Jim Bale, Michael Bamshad, Deborah Barbouth, Pinar Bayrak-Toydemir, Anita Beck, Alan H Beggs, Edward Behrens, Gill Bejerano, Hugo J Bellen, Jimmy Bennett, Jonathan A Bernstein, Gerard T Berry, Anna Bican, Stephanie Bivona, Elizabeth Blue, John Bohnsack, Devon Bonner, Nicholas Borja, Lorenzo Botto, Lauren C Briere, Elizabeth A Burke, Lindsay C Burrage, Manish J Butte, Peter Byers, William E Byrd, Kaitlin Callaway, John Carey, George Carvalho, Thomas Cassini, Sirisak Chanprasert, Hsiao-Tuan Chao, Ivan Chinn, Gary D Clark, Terra R Coakley, Laurel A Cobban, Joy D Cogan, Matthew Coggins, F Sessions Cole, Brian Corner, Rosario I Corona, William J Craigen, Andrew B Crouse, Vishnu Cuddapah, Michael Cunningham, Precilla D’Souza, Hongzheng Dai, Kahlen Darr, Surendra Dasari, Joie Davis, Margaret Delgado, Esteban C Dell’Angelica, Katrina Dipple, Daniel Doherty, Naghmeh Dorrani, Jessica Douglas, Emilie D Douine, Dawn Earl, Lisa T Emrick, Christine M Eng, Kimberly Ezell, Elizabeth L Fieg, Paul G Fisher, Brent L Fogel, Jiayu Fu, William A Gahl, Rebecca Ganetzky, Emily Glanton, Ian Glass, Page C Goddard, Joanna M Gonzalez, Andrea Gropman, Meghan C Halley, Rizwan Hamid, Neal Hanchard, Kelly Hassey, Nichole Hayes, Frances High, Anne Hing, Fuki M Hisama, Ingrid A Holm, Jason Hom, Martha Horike-Pyne, Alden Huang, Yan Huang, Anna Hurst, Wendy Introne, Gail P Jarvik, Jeffrey Jarvik, Suman Jayadev, Orpa Jean-Marie, Vaidehi Jobanputra, Emerald Kaitryn, Oguz Kanca, Yigit Karasozen, Shamika Ketkar, Dana Kiley, Gonench Kilich, Eric Klee, Shilpa N Kobren, Isaac S Kohane, Jennefer N Kohler, Bruce Korf, Susan Korrick, Deborah Krakow, Elijah Kravets, Seema R Lalani, Christina Lam, Brendan C Lanpher, Ian R Lanza, Kumarie Latchman, Kimberly LeBlanc, Brendan H Lee, Richard A Lewis, Pengfei Liu, Nicola Longo, Joseph Loscalzo, Richard L Maas, Ellen F Macnamara, Calum A MacRae, Valerie V Maduro, AudreyStephannie Maghiro, Rachel Mahoney, May Christine V Malicdan, Rong Mao, Ronit Marom, Gabor Marth, Beth A Martin, Martin G Martin, Julian A Martínez-Agosto, Shruti Marwaha, Allyn McConkie-Rosell, Alexa T McCray, Matthew Might, Mohamad Mikati, Danny Miller, Ghayda Mirzaa, Breanna Mitchell, Paolo Moretti, Marie Morimoto, John J Mulvihill, Lindsay Mulvihill, Mariko Nakano-Okuno, Stanley F Nelson, Serena Neumann, Donna Novacic, Devin Oglesbee, James P Orengo, Laura Pace, Stephen Pak, J Carl Pallais, Neil H Parker, LéShon Peart, Leoyklang Petcharet, John A Phillips III, Filippo Pinto e Vairo, Jennifer E Posey, Lorraine Potocki, Barbara N Pusey Swerdzewski, Aaron Quinlan, Daniel J Rader, Ramakrishnan Rajagopalan, Deepak A Rao, Anna Raper, Wendy Raskind, Adriana Rebelo, Chloe M Reuter, Lynette Rives, Amy K Robertson, Lance H Rodan, Martin Rodriguez, Jill A Rosenfeld, Elizabeth Rosenthal, Francis Rossignol, Maura Ruzhnikov, Marla Sabaii, Jacinda B Sampson, Timothy Schedl, Lisa Schimmenti, Kelly Schoch, Daryl A Scott, Elaine Seto, Vandana Shashi, Emily Shelkowitz, Sam Sheppeard, Jimann Shin, Edwin K Silverman, Giorgio Sirugo, Kathy Sisco, Tammi Skelton, Cara Skraban, Carson A Smith, Kevin S Smith, Lilianna Solnica-Krezel, Ben Solomon, Rebecca C Spillmann, Andrew Stergachis, Joan M Stoler, Kathleen Sullivan, Shirley Sutton, David A Sweetser, Virginia Sybert, Holly K Tabor, Queenie Tan, Amelia L M Tan, Arjun Tarakad, Herman Taylor, Mustafa Tekin, Willa Thorson, Cynthia J Tifft, Camilo Toro, Alyssa A Tran, Rachel A Ungar, Adeline Vanderver, Matt Velinder, Dave Viskochil, Tiphanie P Vogel, Colleen E Wahl, Melissa Walker, Nicole M Walley, Jennifer Wambach, Michael F Wangler, Patricia A Ward, Daniel Wegner, Monika Weisz Hubshman, Mark Wener, Tara Wenger, Monte Westerfield, Matthew T Wheeler, Jordan Whitlock, Lynne A Wolfe, Heidi Wood, Kim Worley, Shinya Yamamoto, Zhe Zhang, Stephan Zuchner.

      • Contributors NAB: Conceptualisation, methodology, data curation, formal analysis, project administration, visualisation, writing—original draft and writing—review and editing. MFZ: Conceptualisation, methodology, data curation, formal analysis, visualisation and writing—review and editing. SB: Investigation, resources, data interpretation and writing—review and editing. LSP: Investigation, resources, project administration and writing—review and editing. SHG: Investigation and formal analysis. GB: Investigation, resources and writing—review and editing. MT: Conceptualisation, methodology, formal analysis, investigation, writing—review and editing, visualisation and supervision.

      • Funding This study was supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health (1U01HG010230)

      • Disclaimer The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

      • Competing interests None declared.

      • Provenance and peer review Not commissioned; externally peer reviewed.

      • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.