Hereditary Spastic Paraplegia Linked to Abnormal Splicing From an <scp> <i>AIMP1</i> </scp> Missense Variant

Hereditary spastic paraplegias (HSP) are a diverse group of neurodegenerative diseases characterized by lower limb spasticity and weakness. To date, over 80 genes have been associated with HSP, but many families remain without a molecular diagnosis. In this study, linkage analysis and whole-exome sequencing (WES) were performed to identify the causal gene in a HSP family with autosomal recessive inheritance. Multipoint linkage analysis revealed a maximum significant multipoint LOD score of 4.6 on chromosome 4. WES analysis focused on this region led to the identification of a homozygous missense variant in AIMP1 (c.223G>A). Minigene assays showed that the presumed missense variant in AIMP1 caused loss of the exon 3 donor splice site. Ultimately, this led to the use of an alternative splice site within the intron and the insertion of a premature stop codon. The identification of a novel AIMP1 causal variant contributes to the growing list of HSP genes. Furthermore, it shows that, considering also previous reported cases, disruption of AIMP1 causes a spectrum of disorders ranging from intellectual disability to more complex neurodegenerative diseases.