Mice with Alopecia, Osteoporosis, and Systemic Amyloidosis Due to Mutation in Zdhhc13, a Gene Coding for Palmitoyl Acyltransferase

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.

The Canonical DHHC Motif Is Not Absolutely Required for the Activity of the Yeast S-acyltransferases Swf1 and Pfa4

“…It should be noted that all three proteins are fully acylated in the presence of WT Swf1, and no acylation is detectable for swf1⌬ strains. develop neuropathological and behavioral features of Huntington disease (41), and mice with a nonsense mutation in this gene present with alopecia, osteoporosis, and systemic amyloidosis (42). Most other PATs with the divergent DHHC motif that we identified have not yet been studied.…”

Palmitoylation in Alzheimer⿿s disease and other neurodegenerative diseases

“…While DHHC17/HIP14 has a number of substrates for palmitoylation, the specific substrates of DHHC13/HIP14L are still limited. DHHC13/HIP14L was only reported to palmitoylate GAD65 [76] , huntingtin [76,229], and SNAP-25 [230]. It was recently reported that the DHHC13/HIP14L-deficient hip14l _ / _ mice exhibited the HD-like progressive neuropathological deficits, including progressive loss of striatal and cortical volume and motor impairment [230].…”

Cyclic Alopecia and Abnormal Epidermal Cornification in Zdhhc13 -Deficient Mice Reveal the Importance of Palmitoylation in Hair and Skin Differentiation

“…We previously reported that Zdhhc13 skc4 mice (MGI: 2671845) generated through N-ethyl-N-nitrosourea (ENU) mutagenesis exhibited alopecia, hyperkeratosis, amyloidosis, and osteoporosis (Saleem et al, 2010). We also reported that Zdhhc13, a novel regulator, regulates postnatal skeletal development and bone mass acquisition via Palmitoylation of MT1-MMP, thus revealing the role of Palmitoylation in the pathogenesis of human osteoporosis (Song et al, 2014).…”

“…The observation of alopecia and hyperkeratosis in mice with a deficiency in DHHC13, a palmitoyl-acyl transferase (Saleem et al, 2010), prompted us to explore the role of palmitoylation in the skin and hair differentiation.…”