Genotype-phenotype correlation of gangliosidosis mutations using in silico tools and homology modeling

Abstract

Gangliosidoses, including GM1-gangliosidosis and GM2-gangliosidosis (Tay-Sachs disease and Sandhoff disease), are lysosomal disorders resulting from enzyme deficiencies and accumulation of gangliosides. Phenotypes of gangliosidoses range from infantile, late-infantile, juvenile, and to the adult form. The genotype-phenotype correlation is essential for prognosis and clinical care planning for patients with a gangliosidosis condition. Previously, we have developed a method to establish the genotype-phenotype correlation of another lysosomal disease, mucopolysaccharidosis type I, with in silico tools. This same method was applied to analyze the genotype and phenotype of 38 patients diagnosed with a gangliosidosis disease in the United States. Out of 40 mutations identified, 3 were novel, including p.Tyr192His and p.Phe556Ser of the GLB1 gene and p.Gly461Val of the HEXA gene. Furthermore, the mutant protein structure of all missense mutations was constructed by homology modeling. A systemic structural analysis of these models revealed the specific mechanisms of how each mutation may lead to the disease. In summary, the method developed in this study holds promise as a tool that can be broadly applicable to other lysosomal diseases and monogenic diseases.

Keywords: Disease subtype; Gangliosidosis; Genotype-phenotype correlation; In silico; Lysosomal disorder.

Fig. 1

Close-up view of superimposed structure of native and mutant residues. The main protein core is shown in gray color while the wild-type and mutant residues are shown in red and green color, respectively. The following mutants were shown: p.Arg170Trp, p.Gly123Arg, p.Leu155Arg and p.Tyr270Asp. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

Predicting disease subtypes based on mutations in autosomal recessive diseases. A general protocol for predicting disease subtypes of autosomal recessive diseases was proposed.