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J Invest Dermatol. 2014 Jun;134(6):1589-98. doi: 10.1038/jid.2014.19. Epub 2014 Jan 17.

Palmoplantar keratoderma along with neuromuscular and metabolic phenotypes in Slurp1-deficient mice.

Author information

1
Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
2
Department of Molecular Biology, Genentech, South San Francisco, California, USA.
3
1] Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA [2] Howard Hughes Medical Institute, South San Francisco, California, USA.
4
1] Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA [2] Departments of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.

Abstract

Mutations in SLURP1 cause mal de Meleda, a rare palmoplantar keratoderma (PPK). SLURP1 is a secreted protein that is expressed highly in keratinocytes but has also been identified elsewhere (e.g., spinal cord neurons). Here, we examined Slurp1-deficient mice (Slurp1(-/-)) created by replacing exon 2 with β-gal and neo cassettes. Slurp1(-/-) mice developed severe PPK characterized by increased keratinocyte proliferation, an accumulation of lipid droplets in the stratum corneum, and a water barrier defect. In addition, Slurp1(-/-) mice exhibited reduced adiposity, protection from obesity on a high-fat diet, low plasma lipid levels, and a neuromuscular abnormality (hind-limb clasping). Initially, it was unclear whether the metabolic and neuromuscular phenotypes were due to Slurp1 deficiency, because we found that the targeted Slurp1 mutation reduced the expression of several neighboring genes (e.g., Slurp2, Lypd2). We therefore created a new line of knockout mice (Slurp1X(-/-) mice) with a simple nonsense mutation in exon 2. The Slurp1X mutation did not reduce the expression of adjacent genes, but Slurp1X(-/-) mice exhibited all of the phenotypes observed in the original line of knockout mice. Thus, Slurp1 deficiency in mice elicits metabolic and neuromuscular abnormalities in addition to PPK.

PMID:
24499735
PMCID:
PMC4214150
DOI:
10.1038/jid.2014.19
[Indexed for MEDLINE]
Free PMC Article
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