Clinical and genetic analysis of ATP13A2 in hereditary spastic paraplegia expands the phenotype

Abstract

Background: Hereditary spastic paraplegias (HSP) are neurodegenerative disorders characterized by lower limb spasticity and weakness, with or without additional symptoms. Mutations in ATP13A2, known to cause Kufor-Rakeb syndrome (KRS), have been recently implicated in HSP.

Methods: Whole-exome sequencing was done in a Canada-wide HSP cohort.

Results: Three additional patients with homozygous ATP13A2 mutations were identified, representing 0.7% of all HSP families. Spastic paraplegia was the predominant feature, all patients suffered from psychiatric symptoms, and one patient had developed seizures. Of the identified mutations, c.2126G>C;(p.[Arg709Thr]) is novel, c.2158G>T;(p.[Gly720Trp]) has not been reported in ATP13A2-related diseases, and c.2473_2474insAAdelC;p.[Leu825Asnfs*32]) has been previously reported in KRS but not in HSP. Structural analysis of the mutations suggested a disruptive effect, and enrichment analysis suggested the potential involvement of specific pathways.

Conclusion: Our study suggests that in HSP patients with psychiatric symptoms, ATP13A2 mutations should be suspected, especially if they also have extrapyramidal symptoms.

Keywords: ATP13A2; HSP; Neurodegeneration; Parkinsonism.

Figure 1

In silico analysis of ATP13A2. (a) Network analysis demonstrated that ATP13A2 is associated with other HSP‐related proteins. Green: putative homologs are comentioned or coexpressed in other species, purple: shared protein domains, brown: genetic interactions, blue: colocalization, red: coexpression. (b) Conservation of the residues harboring missense mutations in the ATP13A2 protein. (c) Cartoon representation of human ATP13A2 a.a. 138–1180. The position of the cytosolic A‐, P‐, and N‐domains, and transmembrane (TM) helices are indicated. Lys654 is an invariant lysine that interacts with the adenine ring of ATP prior to the g‐phosphate transfer. Glu348 is the catalytic glutamate in the invariant TGE motif. The HSP mutation sites p.(Arg709Thr) and p.(Gly720Trp) are underlined. The segment consisting of a.a. 826–1180 (cyan) would be deleted in the p.(Leu825Asnfs*32) mutation. (d) Arg709 is located in the N‐domain, on the opposite side of the ATP‐binding site. The mutation p.(Arg709Thr) would result in the loss of a favorable electrostatic interaction, which would destabilize the N‐domain. (e) Gly720 is located in the middle of a β‐strand in the N‐domain. The mutation p.(Gly720Trp) would create significant steric clashes (red), thus likely unfolding the N‐domain. (f) Schematic representation of the location of ATP13A2 mutations in HSP, ALS, KRS, and NCL patients reported so far (Park et al., 2015; Spataro et al., 2019). The top schematic represents the ATP13A2 protein. Functional domains, including the P‐5 ATPase, E1‐E2 ATPase, and hydrolase domains, are indicated with vertical lines. Mutations associated with HSP are indicated in black (mutations identified in this study are circled), ALS in blue, KRS in red, and NCL in yellow. The bottom schematic represents the cDNA of ATP13A2. Exons are delineated with vertical line, and the location of the transmembrane domains are colored in blue

Figure 2

MRI images, pedigrees, and Sanger sequencing chromatograms. (a) Patient A’s MRI showed diffuse cerebellar atrophy (arrow). (b) Patient B’s MRI showed moderate diffuse cerebral and cerebellar atrophy (arrows). (c) MRI and DNA for sanger sequencing were not available for patient C