Identification on new loci, genes, and mutations responsible for hereditary spastic paraplegia

Abstract

Hereditary Spastic Paraplegia (HSP), characterized by lower limb spasticity and progressive weakness, is a group of inherited neurodegenerative disorders. 47 of the 63 genes responsible for HSP, have been associated with autosomal recessive (AR) HSP. In this study, whole exome sequencing analysis was performed for one patient from each 27 ARHSP families to identify causative genes. When WES data was not informative, homozygosity mapping was performed by using WES and/or whole genome SNP genotyping data. After segregation analyses of candidate variants, the causative variants were identified in fifteen families. SPG11 gene was causative in four families. Single families had mutations in CYP7B1 (SPG5A), SPG7, SPG15, and ALS2 genes. SACS and CYP27A1 genes that are associated with Charlevoix-Saguenay Spastic Ataxia and CTX, respectively were determined as the causative genes in two families providing differential diagnosis to these families. KIF1C (SPG58) (Caballero-Oteyza et al., 2014) and PLA2G6 genes (Ozes et al., 2017) identified in two families were reported as novel HSP genes. SAMHD1, ATAD1, and SEMA3C were identified as strong HSP gene candidates. Immortalized B-lymphocytes derived from family members were analyzed to unravel the involvement of candidate HSP genes on disease pathogenesis. ATAD1, SAMHD1 and CYP27A1 protein levels were shown to be reduced in immortalized cell lines of patients. This study contributed to understanding of the genetic heterogeneity of HSP by identifying five novel HSP genes, one of which locates to SPG27. We also underlined the importance of genetic analysis for differential diagnosis, and the necessity of primary genetic screening of SPG11 in AR-HSP-TCC and CYP7B1 in pure AR-HSP cases highlighting the effect of correct genotype-phenotype correlation.