Abstract
Protein palmitoylation has emerged as an important mechanism for regulating protein trafficking, stability, and protein–protein interactions; however, its relevance to disease processes is not clear. Using a genome-wide, phenotype driven N-ethyl-N-nitrosourea–mediated mutagenesis screen, we identified mice with failure to thrive, shortened life span, skin and hair abnormalities including alopecia, severe osteoporosis, and systemic amyloidosis (both AA and AL amyloids depositions). Whole-genome homozygosity mapping with 295 SNP markers and fine mapping with an additional 50 SNPs localized the disease gene to chromosome 7 between 53.9 and 56.3 Mb. A nonsense mutation (c.1273A>T) was located in exon 12 of the Zdhhc13 gene (Zinc finger, DHHC domain containing 13), a gene coding for palmitoyl transferase. The mutation predicted a truncated protein (R425X), and real-time PCR showed markedly reduced Zdhhc13 mRNA. A second gene trap allele of Zdhhc13 has the same phenotypes, suggesting that this is a loss of function allele. This is the first report that palmitoyl transferase deficiency causes a severe phenotype, and it establishes a direct link between protein palmitoylation and regulation of diverse physiologic functions where its absence can result in profound disease pathology. This mouse model can be used to investigate mechanisms where improper palmitoylation leads to disease processes and to understand molecular mechanisms underlying human alopecia, osteoporosis, and amyloidosis and many other neurodegenerative diseases caused by protein misfolding and amyloidosis.
Highlights
Proteins can be modified by a variety of lipids, including myristate (C14), farnesyl (C15), palmitate (C16), geranylgeranyl (C20) and glycosylphosphatidylinositol (GPI)
We reported that mice with mutation in Zdhhc13, a gene coding for palmitoyl acyltransferase that catalyzes the reaction of protein palmitoylation, exhibited a severe phenotype and profound pathology involving multi-organ/systems
These mice showed wasting, weight loss, hair loss, reduced bone mineral density, and generalized amyloid deposition, which resulted in early death
Summary
Proteins can be modified by a variety of lipids, including myristate (C14), farnesyl (C15), palmitate (C16), geranylgeranyl (C20) and glycosylphosphatidylinositol (GPI). Palmitoylation is one of the most common post-translational lipid modifications that involve the addition of palmitate to specific cysteine residues of proteins via a thioester linkage [1,2,3]. Most of the lipid modifications are irreversible, protein S-palmitoylation can be either permanent or transient, which allows it to dynamically regulate protein function [1,4]. Numerous soluble and integral membrane proteins have been shown to be palmitoylated including signaling proteins, enzymes, scaffolding proteins, ion channels, cell adhesion molecules and neuronal proteins. Palmitoyl post-translational modification has recently emerged as an important mechanism for modulating protein targeting, trafficking, stability and protein-protein interactions, and plays roles in numerous cellular processes, including signaling, apoptosis and neuronal transmission [1,3]
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