Genotype-phenotype correlations of KIF5A stalk domain variants

Abstract

The kinesin family member 5A (KIF5A) motor domain variants are typically associated with hereditary spastic paraplegia (HSP) or Charcot-Marie-Tooth 2 (CMT2), while KIF5A tail variants predispose to amyotrophic lateral sclerosis (ALS) and neonatal intractable myoclonus. Variants within the stalk domain of KIF5A are relatively rare. We describe a family of three patients with a complex HSP phenotype and a likely pathogenic KIF5A stalk variant. More family members were reported to have walking difficulties. When reviewing the literature on KIF5A stalk variants, we found 22 other cases. The phenotypes varied with most cases having (complex) HSP/CMT2 or ALS. Symptom onset varied from childhood to adulthood and common additional symptoms for HSP are involvement of the upper limbs, sensorimotor polyneuropathy, and foot deformities. We conclude that KIF5A variants lead to a broad clinical spectrum of disease. Phenotype distribution according to variants in specific domains occurs often in the motor and tail domain but are not definite. However, variants in the stalk domain are not bound to a specific phenotype.

ALS-linked KIF5A ΔExon27 mutant causes neuronal toxicity through gain of function

“…These results support the idea that the new C-terminal tail in ΔExon27 is required to confer gain of toxicity through the relief of autoinhibition and through self-association/aggregation of the mutant motors. In line with this notion, several single nucleotide deletion variants of KIF5A have also been identified in ALS patients (de Boer et al , 2021) which result in a C-terminal tail similar to that of the exon 27-skiping variants: Variants c2987delA (p.Asp996fs), c.2989delA (p.Asn997fs), and c.2996delA (p.Asn999fs) cause one nucleotide frame shifting at amino acid positions Asp996, Asn997, and Asn999 at the protein level, respectively ( Fig. S5 ).…”

Characterizing SOD1 mutations in Spain: The impact of genotype, age and sex in the natural history of the disease

“…Some studies had reported SOD1 mutations in patients with atypical phenotypes suggestive of pSMA, dSMA, CMT or spastic paraplegia [20,[23][24][25][26], but this study confirms a causal role. Thus, SOD1 should join the list of genes that can present with a wide spectrum of motor phenotypes (such as KIF5A, CHCHD10, VAPB, FIG4) [7,27,28], where its analysis should also be considered.…”

“…The causes of this pleiotropy are not entirely known. In some genes, a mutational hotspot predisposes to one or another phenotype [27]. In other genes it seems more dependent on other genetic or epigenetic factors because the same mutation can present with different phenotypes in diverse populations [7,28].…”

Axon Biology in ALS: Mechanisms of Axon Degeneration and Prospects for Therapy

“…Among these, the anterograde axonal transport motor KIF5A stands out as a risk factor for the survival of long axons in multiple disorders, including hereditary spastic paraplegia (HSP) [ 95 ], Charcot-Marie-Tooth (CMT) disease Type 2 [ 96 ], adult onset distal SMA [ 97 ], and possibly neonatal intractable myoclonus [ 98 ], although whether this last one involves axon loss is less clear. Intriguingly, there may be a degree of domain specificity regarding which KIF5A variant contributes to which disorder, with motor domain variants predominantly linked to HSP and CMT2 and tail (cargo-binding) domain variants to ALS and neonatal intractable myoclonus, although there are exceptions [ 99 ]. Nevertheless, the phenotype of the null mice, and their neurons in primary culture [ 100 ] clearly indicate that KIF5A is essential for both axonal transport and the ability to sustain long axons.…”