Dominant KPNA3 Mutations Cause Infantile‐Onset Hereditary Spastic Paraplegia

Abstract

Objective: Hereditary spastic paraplegia (HSP) is a highly heterogeneous neurologic disorder characterized by lowerextremity spasticity. Here, we set out to determine the genetic basis of an autosomal dominant, pure, and infantileonset form of HSP in a cohort of 8 patients with a uniform clinical presentation. Methods: Trio whole-exome sequencing was used in 5 index patients with infantile-onset pure HSP to determine the genetic cause of disease. The functional impact of identified genetic variants was verified using bioinformatics and complementary cellular and biochemical assays. Results: Distinct heterozygous KPNA3 missense variants were found to segregate with the clinical phenotype in 8 patients; in 4 of them KPNA3 variants had occurred de novo. Mutant karyopherin-α3 proteins exhibited a variable pattern of altered expression level, subcellular distribution, and protein interaction. Interpretation: Our genetic findings implicate heterozygous variants in KPNA3 as a novel cause for autosomal dominant, early-onset, and pure HSP. Mutant karyopherin-α3 proteins display varying deficits in molecular and cellular functions, thus, for the first time, implicating dysfunctional nucleocytoplasmic shuttling as a novel pathomechanism causing HSP.

Prenatal diagnosis of pontocerebellar hypoplasia with postnatal follow‐up

“…36 KPNA3 was the causative gene in one of the cases of our series: KPNA3 is a gene involved in neurodevelopmental disorder with spastic paraplegia that could be complex, and in which the hypoplastic cerebellum and brainstem have been described. 37 Genetic identification can help refine the neurological prognosis by distinguishing "fixed" neurological pathologies, most often related to chromosomal abnormalities, from "neurodegenerative" diseases, which are more severe and progressive. A few rare situations of dominant transmission (such as DLL1 in our series) are important to highlight.…”

Communicating pain: emerging axonal signaling in peripheral neuropathic pain

“…Importins ɑ1 and ɑ5 were also found to bind viral proteins to aid viral replication of herpes simplex virus and Newcastle disease virus, respectively ( Döhner et al, 2018 ; Duan et al, 2018 ). Interestingly, mutant importin ɑ4 can cause Infantile-Onset Hereditary Spastic Paraplegia, though the molecular mechanism is unclear ( Schob et al, 2021 ). Importin ɑ3 was recently found to be relevant for persistence of chronic NeuP ( Marvaldi et al, 2020 ).…”

Alu Retrotransposition Event in SPAST Gene as a Novel Cause of Hereditary Spastic Paraplegia

“…1 More than 80 spastic paraplegia genes (SPGs) and associated loci have been identified. 2 Spastic paraplegia type 4 (SPG4) is the most common HSP subtype, accounting for 15% to 40% of all HSPs. 3 Most patients with SPG4 present clinically with prototypical pure HSP.…”

“…HSP is distinguished as pure or complicated forms according to the presence of additional neurological symptoms, such as cognitive impairment, ataxia, neuropathy, or seizures 1 . More than 80 spastic paraplegia genes (SPGs) and associated loci have been identified 2 . Spastic paraplegia type 4 (SPG4) is the most common HSP subtype, accounting for 15% to 40% of all HSPs 3 .…”