Chiranjeevi Bodda, Moneef Shoukier, Shyamal Mosalaganti, Inga Zerr, Maren Breithaupt, Sara M Pilgram and Ashraf U Mannan
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.
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