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

Li Ou, Sarah Kim, Chester B Whitley, Jeanine R. Jarnes-Utz

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish (US)
Article number100495
JournalMolecular Genetics and Metabolism Reports
Volume20
DOIs
StatePublished - Sep 2019

Bibliographical note

Funding Information:
This work is supported by NIH grant P01HD032652. Dr. Li Ou is a fellow of the Lysosomal Disease Network (U54NS065768). The Lysosomal Disease Network is a part of the Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), and NCATS. This consortium is funded through a collaboration between NCATS, the National Institute of Neurological Disorders and Stroke (NINDS), and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

Funding Information:
This work is supported by NIH grant P01HD032652 . Dr. Li Ou is a fellow of the Lysosomal Disease Network ( U54NS065768 ). The Lysosomal Disease Network is a part of the Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), and NCATS. This consortium is funded through a collaboration between NCATS , the National Institute of Neurological Disorders and Stroke (NINDS), and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

Publisher Copyright:
© 2019 The Authors

Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.

Keywords

  • Disease subtype
  • Gangliosidosis
  • Genotype-phenotype correlation
  • In silico
  • Lysosomal disorder

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