Perspectives into the spatial organization of HGSNAT protein structure for Sanfilippo syndrome type C (MPS IIIC)

Sanfilippo syndrome type C, also known as mucopolysaccharidosis type IIIC (MPS IIIC), is an inborn error of metabolism, with an incidence of 0.17 per 100.000 live births, characterized by the deficiency of heparan-alpha-glucosaminide N-acetyltransferase (HGSNAT) enzymatic activity. Unlike other MPSs, therapies such as enzyme replacement and gene therapy are not available for MPS IIIC due to a discrepancy in the biological structural information of the enzyme, among other reasons. HGSNAT is a trans-membranal lysosomal enzyme characterized with an intra-lysosomal enzymatic domain that to date, lacks a crystallographic structure. Considering that little is known about the enzymatic structure and trans-membrane proteins represent a challenge for crystallographic methods, this work aimed to update the state-of-the-art HGSNAT structural information using a computational approach. We performed a structural characterization of the canonical protein sequence presenting a novel protein organization. Accordingly, we aimed to understand the role of punctual mutations in the presented novel protein organization. We explored the putative effect of 37 missense and nonsense mutations reported worldwide across the new protein organization. To do so we performed a functional characterization of the mutations, mapped the mutation location and predicted the phenotypic implications. Hereby, we present a robust structural characterization of HGSNAT coupled with mutation mapping and phenotype prediction. To this end, this work presents a novel HGSNAT two-dimensional organization allowing the prediction of the involvement of mutations on the enzymatic activity.