Identification of modifier genes/networks of lysosomal biology
Date
2023
Type:
Thesis
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65 p.
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Acceso abierto
Authors
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Publisher
Universidad del Desarrollo. Facultad de Medicina
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Abstract
Lysosomal storage diseases (LSDs) are a heterogeneous group of ~70 rare inherited metabolic diseases caused by loss-of-function variants in genes encoding for lysosomal enzymes, their activators, or transport proteins. Clinical symptoms manifest during early childhood or adolescence, causing varying degrees of disability and short life expectancies. At a cellular level, LSD cells show a progressive accumulation of undegraded substrates. In a subset of LSDs, called sphingolipidosis, the primary buildup material corresponds to lipids. These diseases can affect several organs, including the liver, brain, heart, peripheral nervous system, haematologic, skeletal, gastrointestinal system, lung, muscle, and others. On the other hand, defects in processing sphingolipids have also been observed in patients with common diseases such as neurodegenerative disorders and cancer. To date, the phenotypic variability observed in monogenic conditions is thought to be influenced by genomic loci variation other than in the primary disease locus. These genes are called modifiers. We harnessed the natural genetic variation between different strains of healthy mice to identify modifier genes/networks of lysosomal biology. We used a systems genetics approach. We measured the hepatic activity of 12 lysosomal enzymes and several of their natural substrates in livers derived from a panel of inbred mouse strains, followed by genetic regulators mapping by genome-wide association studies (GWAS), transcriptome associations, Bayesian integration, and pathway enrichment analysis. The GWA study identified 137 non-redundant genes associated with changes in lysosomal enzyme activities and 1744 modifiers for GSLs. Among these genes, 30 are shared between the enzymes and lipid groups. They are clustered into three pathways and associated with other nonLSD diseases. Surprisingly, they are under the regulation of ten common transcription factors, suggesting a common regulation of sphingolipid metabolism. In summary, we have identified novel regulators of lysosomal enzymes and GSL levels that may serve as therapeutic targets for LSD and implicated GSL metabolism in other diseases.
Description
A thesis submitted to the School of Medicine, Clínica AlemanaUniversidad del Desarrollo to attain the degree of Doctor (PhD) in Sciences and Innovation in Medicine
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Citation
Keywords
Systems genetics, Inbred strains, Modifier genes, Lysosomal enzyme activity, Glycosphingolipids, Disorders with lysosomal dysfunction, 090036S