In-Frame Insertion Mutation in the SPG11 Gene Causes Autosomal Recessive Spastic Paraplegia with Thin Corpus Callosum “In A” Turkish Family with Late Age of Onset of the Phenotype

Abstract

Autosomal recessive hereditary spastic paraplegia with thin corpus callosum (ARHSP-TCC) is one of the most prevalent forms of complex ARHSP. Mutations in the SPG11 gene are the most common cause for ARHSP-TCC and accounts for up to 70% of all cases. The mutational spectrum of SPG11 gene is broad as all types of DNA alterations are detected in the gene and most mutations lead to a premature truncation of the protein, suggesting “loss of function” as the likely pathogenic mechanism. In the current study, we report a consanguineous Turkish family with ARHSP inheritance manifesting white matter abnormalities including TCC with relatively late age of onset. Sequencing of SPG11 gene revealed a homozygous insertion of 15 nucleotides at position 6886 in exon 38 (c.6886_6900Dup15) leading to an in-frame insertion of five amino acids at codon 2296 (p.K2296_L2300Dup5), which resides within a predicted, highly conserved, intradiol ring-cleavage dioxygenase domain (2104 -2381 residues). In silico structural prediction of intradiol domain of the mutated Spatacsin protein revealed that the duplication of five amino acids leads to an extra turn in α-helix and a slightly longer loop region. Our structural analysis suggests that it is unlikely that insertion mutation (c.6886_6900Dup15) causes dysfunctional protein rather the minor conformation changes may elicit a “gain of function”, which may be detrimental to endogenous function of Spatacsin thus cause HSP.