Exploring genetic modifiers of Gaucher disease: The next horizon

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.

Keywords: Gaucher disease; Mendelian disorders; Parkinson disease; genetic modifiers; genotype-phenotype correlation; glucocerebrosidase.

Figure 1.

Methods for and challenges of discovering modifiers, incorporating the influence of effect size and allele frequency. Rare or common variants with a large effect size (green) can often be appreciated through linkage and association studies. GWAS can often successfully identify common variants (yellow), even those with a small effect. However rare or low frequency variants with a small or intermediate effect size (red) can often prove difficult to identify, and techniques for their detection are in development/refinement. Adapted from McCarthy et al., 2008 and Manolio et al., 2009.

Figure 2.

Scaled map of a 90kb gene-rich region surrounding GBA1. Genes represented above the line are transcribed right to left, while the genes below are transcribed left to right. Adapted from Winfield et al., 1997.

Figure 3.

Potential genetic modifiers and the proposed mechanisms by which they may regulate clinical outcome of Gaucher disease.