Genotype and defects in microtubule-based motility correlate with clinical severity in KIF1A-associated neurological disorder

HGG Adv. 2021 Apr 8;2(2):100026. doi: 10.1016/j.xhgg.2021.100026.

Lia Boyle ¹, Lu Rao ², Simranpreet Kaur ³, Xiao Fan ¹ ⁴, Caroline Mebane ¹, Laura Hamm ⁵, Andrew Thornton ⁶, Jared T Ahrendsen ⁷, Matthew P Anderson ⁷ ⁸ ⁹ ¹⁰, John Christodoulou ³, Arne Gennerich ², Yufeng Shen ⁴ ¹¹, Wendy K Chung ¹ ¹²

Affiliations

1 Department of Pediatrics, Columbia University Irving Medical Center, New York, NY 10032, USA.
2 Department of Anatomy and Structural Biology and Gruss Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
3 Murdoch Children's Research Institute, Parkville, Department of Pediatrics, University of Melbourne, Melbourne, VIC 3052, Australia.
4 Department of Systems Biology, Columbia University Irving Medical Center, New York, NY 10032, USA.
5 Genetic & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
6 Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA.
7 Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
8 Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
9 Boston Children's Hospital Intellectual and Developmental Disabilities Research Center, 300 Longwood Avenue, Boston, MA 02115, USA.
10 Program in Neuroscience, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
11 Department of Biomedical Informatics, Columbia University Irving Medical Center, New York, NY 10032, USA.
12 Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA.

PMID: 33880452 DOI: 10.1016/j.xhgg.2021.100026

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 protein. We found increased severity is strongly associated with variants occurring in protein regions involved with ATP and MT binding: the P loop, switch I, and switch II. For a subset of variants, we generated recombinant proteins, which we used to assess transport in vivo by assessing neurite tip accumulation and to assess MT binding, motor velocity, and processivity using total internal reflection fluorescence microscopy. We find all modeled variants result in defects in protein transport, and we describe three classes of protein dysfunction: reduced MT binding, reduced velocity and processivity, and increased non-motile rigor MT binding. The rigor phenotype is consistently associated with the most severe clinical phenotype, while reduced MT binding is associated with milder clinical phenotypes. Our findings suggest the clinical phenotypic heterogeneity in KAND likely reflects and parallels diverse molecular phenotypes. We propose a different way to describe KAND subtypes to better capture the breadth of disease severity.

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