Mice with alopecia, osteoporosis, and systemic amyloidosis due to mutation in Zdhhc13, a gene coding for palmitoyl acyltransferase
| Autor: | Jeffrey J.Y. Yen, Yuan-Tsong Chen, Li-Fen Shen, Jer-Yuarn Wu, Hong-Wen Huang, I-Wen Song, Ya-Wen Hsiao, Chen-Pei D. Tu, Kai-Ming Liu, Amir N. Saleem, Yen-Hui Chen, Hwa Jin Baek, Hsiao-Jung Kao, Monica J. Justice, Tateki Kikuchi |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Cancer Research
Aging lcsh:QH426-470 Nonsense mutation Radiology and Medical Imaging/Ultrasonography Single-nucleotide polymorphism Biology Biochemistry/Protein Folding 03 medical and health sciences Mice 0302 clinical medicine Palmitoylation Genetics medicine Animals Protein palmitoylation Palmitoyl acyltransferase Molecular Biology Genetics (clinical) Ecology Evolution Behavior and Systematics 030304 developmental biology Regulation of gene expression Genetics and Genomics/Medical Genetics 0303 health sciences Base Sequence Amyloidosis Genetics and Genomics Genetics and Genomics/Gene Expression Alopecia medicine.disease Immunohistochemistry 3. Good health Genetics and Genomics/Gene Function lcsh:Genetics Phenotype Genetics and Genomics/Disease Models Gene Expression Regulation Organ Specificity 030220 oncology & carcinogenesis Mutation Osteoporosis DHHC domain Acyltransferases Research Article |
| Zdroj: | PLoS Genetics, Vol 6, Iss 6, p e1000985 (2010) PLoS Genetics |
| ISSN: | 1553-7404 1553-7390 |
| Popis: | 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. Author Summary Palmitoylation, the addition of palmitate (a fatty acid) to protein, is one of the most common post-translational lipid modifications and has recently emerged as an important mechanism for modulating protein targeting, trafficking, stability, and protein–protein interactions. However, its physiological role and its relevance to the disease processes are not at all clear. Here 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 (alopecia), reduced bone mineral density (osteoporosis), and generalized amyloid deposition, which resulted in early death. Our results established a direct link between protein palmitoylation and regulation of the important diverse physiological functions and indicated that its absence can result in profound disease pathology. This mouse model will be useful for further understanding the molecular mechanisms underlying human alopecia, osteoporosis, and many other neurodegenerative diseases caused by protein misfolding and amyloid deposition. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|