Exploring genetic modifiers of Gaucher disease: The next horizon. Issue 12 (11th September 2018)

• Record Type: Journal Article
• Authors: Davidson, Brad A.; Hassan, Shahzeb; Garcia, Eric Joshua; Tayebi, Nahid; Sidransky, Ellen
• Is Part Of: Human mutation. Volume 39:Issue 12(2018)
• Page Start: 1739
• Page End: 1751
• Publication Date: 2018-09-11
• Subjects: Gaucher disease -- genetic modifiers -- genotype–phenotype correlation -- glucocerebrosidase -- Mendelian disorders -- Parkinson disease; Human chromosome abnormalities -- Periodicals; Mutation (Biology) -- Periodicals; 616.04205
• DOI: 10.1002/humu.23611
• Languages: English
• ISSNs: 1059-7794

Abstract

Abstract: Gaucher disease is an autosomal recessive lysosomal storage disorder resulting from mutations in the gene GBA1 that lead to a deficiency in the enzyme glucocerebrosidase. Accumulation of the enzyme's substrates, glucosylceramide and glucosylsphingosine, results in symptoms ranging from skeletal and visceral involvement to neurological manifestations. Nonetheless, there is significant variability in clinical presentations amongst patients, with limited correlation between genotype and phenotype. Contributing to this clinical variation are genetic modifiers that influence the phenotypic outcome of the disorder. In this review, we explore the role of genetic modifiers in Mendelian disorders and describe methods to facilitate their discovery. In addition, we provide examples of candidate modifiers of Gaucher disease, explore their relevance in the development of potential therapeutics, and discuss the impact of GBA1 and modifying mutations on other more common diseases like Parkinson disease. Identifying these important modulators of Gaucher phenotype may ultimately unravel the complex relationship between genotype and phenotype and lead to improved counseling and treatments. Abstract : Gaucher disease is an autosomal recessive lysosomal storage disorder resulting from mutations in the gene GBA, leading to deficiency in the enzyme glucocerebrosidase. This disease presents with clinical heterogeneity likely due to, at least in part, genetic modifiers which influence phenotypic outcome. In this review, we examine the impacts of genetic modifiers on Gaucher disease presentation and highlight the importance of ongoing research in this field to understand variability and provide pathways for treatment in all disorders termed monogenic.