Abstract
Mucopolysaccharidosis (MPS) IIIA, also known as Sanfilippo syndrome type A, is a severe, progressive disease that affects the central nervous system (CNS). MPS IIIA is inherited in an autosomal recessive manner and is caused by a deficiency in the lysosomal enzyme sulfamidase, which is required for the degradation of heparan sulfate. The sulfamidase is produced by the N-sulphoglucosamine sulphohydrolase (SGSH) gene. In MPS IIIA patients, the excess of lysosomal storage of heparan sulfate often leads to mental retardation, hyperactive behavior, and connective tissue impairments, which occur due to various known missense mutations in the SGSH, leading to protein dysfunction. In this study, we focused on three mutations (R74C, S66W, and R245H) based on in silico pathogenic, conservation, and stability prediction tool studies. The three mutations were further subjected to molecular dynamic simulation (MDS) analysis using GROMACS simulation software to observe the structural changes they induced, and all the mutants exhibited maximum deviation patterns compared with the native protein. Conformational changes were observed in the mutants based on various geometrical parameters, such as conformational stability, fluctuation, and compactness, followed by hydrogen bonding, physicochemical properties, principal component analysis (PCA), and salt bridge analyses, which further validated the underlying cause of the protein instability. Additionally, secondary structure and surrounding amino acid analyses further confirmed the above results indicating the loss of protein function in the mutants compared with the native protein. The present results reveal the effects of three mutations on the enzymatic activity of sulfamidase, providing a molecular explanation for the cause of the disease. Thus, this study allows for a better understanding of the effect of SGSH mutations through the use of various computational approaches in terms of both structure and functions and provides a platform for the development of therapeutic drugs and potential disease treatments.
Highlights
Mucopolysaccharidosis (MPS) IIIA, known as Sanfilippo syndrome type A, is a neurodegenerative lysosomal storage disorder caused by a deficiency in the enzyme N-sulfoglucosamine sulfohydrolase (SGSH, EC:3.10.1.1), which is involved in theMetab Brain Dis (2019) 34:1577–15942014)
The mutations R74C, S66W, and R245H were subjected to pathogenic prediction tools (Meta-SNP) and stability prediction tools (SDM, MUpro, IMutant 3.0)
MPS IIIA is a genetic metabolic disorder characterized by progressive neurodegeneration and behavioral problems
Summary
Mucopolysaccharidosis (MPS) IIIA, known as Sanfilippo syndrome type A, is a neurodegenerative lysosomal storage disorder caused by a deficiency in the enzyme N-sulfoglucosamine sulfohydrolase (SGSH, EC:3.10.1.1), which is involved in theMetab Brain Dis (2019) 34:1577–15942014). Mucopolysaccharidosis (MPS) IIIA, known as Sanfilippo syndrome type A, is a neurodegenerative lysosomal storage disorder caused by a deficiency in the enzyme N-sulfoglucosamine sulfohydrolase (SGSH, EC:3.10.1.1), which is involved in the. The initial symptoms of the disease generally appear in the first to the sixth year of life, and death usually occurs in the early twenties (Valstar et al 2010). The incidences of these subtypes are unevenly distributed. The incidence of MPS IIIA ranges from 0.68 per 100,000 to 1.21 per 100,000 in European countries (Baehner et al 2005; Héron et al 2011). MPS IIIA and MPS IIIB are more common than MPS IIIC and MPS IIID (Valstar et al 2008), whereas MPS IIIA is more severe than MPS IIIB (Buhrman et al 2013)
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