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Mice with alopecia, osteoporosis, and systemic amyloidosis due to mutation in Zdhhc13, a gene coding for palmitoyl acyltransferase.

Publication ,  Journal Article
Saleem, AN; Chen, Y-H; Baek, HJ; Hsiao, Y-W; Huang, H-W; Kao, H-J; Liu, K-M; Shen, L-F; Song, I-W; Tu, C-PD; Wu, J-Y; Kikuchi, T; Justice, MJ ...
Published in: PLoS Genet
June 10, 2010

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.

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Published In

PLoS Genet

DOI

EISSN

1553-7404

Publication Date

June 10, 2010

Volume

6

Issue

6

Start / End Page

e1000985

Location

United States

Related Subject Headings

  • Phenotype
  • Osteoporosis
  • Organ Specificity
  • Mutation
  • Mice
  • Immunohistochemistry
  • Gene Expression Regulation
  • Developmental Biology
  • Base Sequence
  • Animals
 

Citation

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Saleem, A. N., Chen, Y.-H., Baek, H. J., Hsiao, Y.-W., Huang, H.-W., Kao, H.-J., … Chen, Y.-T. (2010). Mice with alopecia, osteoporosis, and systemic amyloidosis due to mutation in Zdhhc13, a gene coding for palmitoyl acyltransferase. PLoS Genet, 6(6), e1000985. https://doi.org/10.1371/journal.pgen.1000985
Saleem, Amir N., Yen-Hui Chen, Hwa Jin Baek, Ya-Wen Hsiao, Hong-Wen Huang, Hsiao-Jung Kao, Kai-Ming Liu, et al. “Mice with alopecia, osteoporosis, and systemic amyloidosis due to mutation in Zdhhc13, a gene coding for palmitoyl acyltransferase.PLoS Genet 6, no. 6 (June 10, 2010): e1000985. https://doi.org/10.1371/journal.pgen.1000985.
Saleem AN, Chen Y-H, Baek HJ, Hsiao Y-W, Huang H-W, Kao H-J, et al. Mice with alopecia, osteoporosis, and systemic amyloidosis due to mutation in Zdhhc13, a gene coding for palmitoyl acyltransferase. PLoS Genet. 2010 Jun 10;6(6):e1000985.
Saleem, Amir N., et al. “Mice with alopecia, osteoporosis, and systemic amyloidosis due to mutation in Zdhhc13, a gene coding for palmitoyl acyltransferase.PLoS Genet, vol. 6, no. 6, June 2010, p. e1000985. Pubmed, doi:10.1371/journal.pgen.1000985.
Saleem AN, Chen Y-H, Baek HJ, Hsiao Y-W, Huang H-W, Kao H-J, Liu K-M, Shen L-F, Song I-W, Tu C-PD, Wu J-Y, Kikuchi T, Justice MJ, Yen JJY, Chen Y-T. Mice with alopecia, osteoporosis, and systemic amyloidosis due to mutation in Zdhhc13, a gene coding for palmitoyl acyltransferase. PLoS Genet. 2010 Jun 10;6(6):e1000985.

Published In

PLoS Genet

DOI

EISSN

1553-7404

Publication Date

June 10, 2010

Volume

6

Issue

6

Start / End Page

e1000985

Location

United States

Related Subject Headings

  • Phenotype
  • Osteoporosis
  • Organ Specificity
  • Mutation
  • Mice
  • Immunohistochemistry
  • Gene Expression Regulation
  • Developmental Biology
  • Base Sequence
  • Animals