Dominant transmission of de novo KIF1A motor domain variant underlying pure spastic paraplegia

Abstract

Variants in family 1 kinesin (KIF1A), which encodes a kinesin axonal motor protein, have been described to cause variable neurological manifestations. Recessive missense variants have led to spastic paraplegia, and recessive truncations to sensory and autonomic neuropathy. De novo missense variants cause developmental delay or intellectual disability, cerebellar atrophy and variable spasticity. We describe a family with father-to-son transmission of de novo variant in the KIF1A motor domain, in a phenotype of pure spastic paraplegia. Structural modeling of the predicted p.(Ser69Leu) amino acid change suggested that it impairs the stable binding of ATP to the KIF1A protein. Our study reports the first dominantly inherited KIF1A variant and expands the spectrum of phenotypes caused by heterozygous KIF1A motor domain variants to include pure spastic paraplegia. We conclude that KIF1A should be considered a candidate gene for hereditary paraplegias regardless of inheritance pattern.

Figure 1

(a) Pedigree of the affected family (proband highlighted with arrow) and (b) Sanger sequencing chromatograms show DNA from the proband (lower), his parents (middle) and paternal grandparents (upper). No evidence of blood DNA mosaicism was detected in the grandparents. (c) Amino acid conservation of the KIF1A motor domain region in which p.S69 is located (arrow).

Figure 2

(a, b) Overall structure of the KIF1A motor domain. Missing loops are indicated by dashed lines. The switch I, switch II, P-loop and neck linker are indicated in blue, magenta, green and yellow, respectively. The location of p.Ser69 and ATP analogue (AMP-PNP, adenylyl imidodiphosphate) are shown. (c, d) Electrocharge distribution of wild-type and p.(Ser69Leu) KIF1A. Negative and positive charges are represented by red and blue color, respectively. (e) ATP binding interface of KIF1A in crystal structure. Phosphate groups are held by several hydrogen bonds (dotted line). p.Tyr105 shows a phi–phi interaction with the adenine group from ATP. p.Tyr67 from the L2 loop shows water-mediated bonding with the N1 of adenine group. (f) Structural impact of p.(Ser69Leu) change. The substitution might affect the stability of the L2 loop and change the conformation of p.Tyr67, disrupting its binding to the adenine group of ATP. (g) Views of the KIF1A ATP binding pocket and (h) the modeled structure of p.(Ser69Leu) variant.