Journal article
Genotype and defects in microtubule-based motility correlate with clinical severity in KIF1A-associated neurological disorder
L Boyle, L Rao, S Kaur, X Fan, C Mebane, L Hamm, A Thornton, JT Ahrendsen, MP Anderson, J Christodoulou, A Gennerich, Y Shen, WK Chung
Human Genetics and Genomics Advances | ELSEVIER | Published : 2021
Abstract
KIF1A-associated neurological disorder (KAND) encompasses a group of rare neurodegenerative conditions caused by variants in KIF1A, a gene that encodes an anterograde neuronal microtubule (MT) motor protein. Here we characterize the natural history of KAND in 117 individuals using a combination of caregiver or self-reported medical history, a standardized measure of adaptive behavior, clinical records, and neuropathology. We developed a heuristic severity score using a weighted sum of common symptoms to assess disease severity. Focusing on 100 individuals, we compared the average clinical severity score for each variant with in silico predictions of deleteriousness and location in the protei..
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Awarded by State Government of Victoria
Funding Acknowledgements
We thank KIF1A.org for their ongoing partnership and Autism Brain Net for the collection of postmortem brain specimens. We thank Scott Robinson, Jennifer Shahar, Emily Horowitz, and Rachel Cogny for their assistance with this project. We thank Kristen Verhey for her assistance with optimizing the neurite tip accumulation and in vitro gliding assays. Molecular graphics were generated with UCSF Chimera, developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco, with support from NIH grant P41GM103311. Support was also received from NIH grants TL1TR001875 (L.B.), R01N114636 (L.R., A.G., and W.K.C.), and UL1TR001873 and from KIF1A.org. Research conducted at the Murdoch Children's Research Institute was supported by the Victorian Government's Operational Infrastructure Support Program.