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Case Reports
. 2025 Jan 27;62(2):117-122.
doi: 10.1136/jmg-2024-109908.

KIF21A-associated peripheral neuropathy defined by impaired binding with TUBB3

Nicholas A Borja  1 , Mohammad Faraz Zafeer  2 , Stephanie Bivona  1 , LéShon Peart  2 , Sakir Humayun Gultekin  3 ; Undiagnosed Diseases Network; Guney Bademci  1 , Mustafa Tekin  4 ; Undiagnosed Diseases Network NIH
Collaborators, Affiliations
Case Reports

KIF21A-associated peripheral neuropathy defined by impaired binding with TUBB3

Nicholas A Borja et al. J Med Genet. .

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.

Keywords: Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Eye Diseases; Human Genetics; Nervous System Diseases.

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Conflict of interest statement

Competing interests: None declared.

Figures

FIGURE 1.
FIGURE 1.
A. Illustration of KIF21A with leucine at amino acid 664 (Leu664) compared to proline at amino acid 664 (Pro664) with predicted salt bridges formed between Leu664 and Leu660, Ile661, Leu756, with a comparison of Pro664 demonstrating a reduction in ionic interactions amongst these residues. B. Predictive modeling of this effect on TUBB3 interaction through comparison of predicted salt bridges formed between KIF21A and TUBB3 originating at KIF21A residues Glu1089, Arg1423, Lys881, and Lys847 (left), with the Pro664 disrupting most of these and producing ionic interactions with TUBB3 at KIF21A residues Lys847, Arg850, Arg851, Lys903, Lys901 and Lys1220 (right). TUBB3 residues depicted in magenta, KIF21A residues in purple. C. Co-immunoprecipitation assay with western blot image demonstrating the presence of TUBB3 protein co-eluted alongside KIF21A protein at 55 kD (*). c-Myc refers to the pure c-Myc peptide used as a kit efficiency control; Con denotes HEK293 cells only; Ref is the reference KIF21A; Var is the KIF21A p.Pro644. D. Relative abundance of eluted TUBB3 compared between KIF21A reference and KIF21A p.Leu664Pro, with bars representing standard error of the mean, ** representing p ≤ 0.01, no. transfections = 3.
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