Palmoplantar Keratoderma in Slurp2-Deficient Mice

Abstract

SLURP1, a member of the Ly6 protein family, is secreted by suprabasal keratinocytes. Mutations in SLURP1 cause a palmoplantar keratoderma (PPK) known as mal de Meleda. Another secreted Ly6 protein, SLURP2, is encoded by a gene located ~20 kb downstream from SLURP1. SLURP2 is produced by suprabasal keratinocytes. To investigate the importance of SLURP2, we first examined Slurp2 knockout mice in which exon 2–3 sequences had been replaced with lacZ and neo cassettes. Slurp2−/− mice exhibited hyperkeratosis on the volar surface of the paws (i.e., PPK), increased keratinocyte proliferation, and an accumulation of lipid droplets in the stratum corneum. They also exhibited reduced body weight and hind limb clasping. These phenotypes are very similar to those of Slurp1−/− mice. To solidify a link between Slurp2 deficiency and PPK and to be confident that the disease phenotypes in Slurp2−/− mice were not secondary to the effects of the lacZ and neo cassettes on Slurp1 expression, we created a new line of Slurp2 knockout mice (Slurp2X−/−) in which Slurp2 was inactivated with a simple nonsense mutation. Slurp2X−/− mice exhibited the same disease phenotypes. Thus, Slurp2 deficiency and Slurp1 deficiencies cause the same disease phenotypes.

Palmoplantar keratoderma in Slurp1/Slurp2 double-knockout mice

“…2b–c). In an earlier study, we found that Krt16 , Lce3a , and Lce3f were expressed at higher levels in the paw skin of Slurp1 −/− mice, while levels of Krt24 and Lce1m expression were reduced [7]. In the current study, we confirmed those gene-expression perturbations, but we found no evidence that the changes were exaggerated in Slurp1 −/− ; Slurp2 −/− mice.…”

“…Recently, we found that inactivation of Slurp2 , which encodes another secreted protein of keratinocytes, causes disease phenotypes that are indistinguishable from those observed in Slurp1 knockout mice ( i.e ., PPK, hind-limb clasping) [7]. These findings were documented in two lines of Slurp2 knockout mice, including one with a simple nonsense mutation in exon 2 of Slurp2 [7].…”

“…These findings were documented in two lines of Slurp2 knockout mice, including one with a simple nonsense mutation in exon 2 of Slurp2 [7]. SLURP1 and SLURP2 are members of the Ly6 superfamily and are predicted to share a three-fingered structural motif, but amino acid sequence identity is minimal [7]. Why deficiencies in two distinct family members would produce virtually identical disease phenotypes is unclear.…”

A hypomorphic Egfr allele does not ameliorate the palmoplantar keratoderma caused by SLURP1 deficiency

“…Treatment of an Olmsted syndrome patient with an EGFR inhibitor (erlotinib) ameliorated the PPK (4). Third, SLURP1 deficiency in mice leads to upregulated expression of keratins 6 and 16 (5), and treatment of keratinocytes with EGFR ligands increases the expression of those same keratins (6). Finally, a deficiency in ERRFI1 (also called mitogen-inducible gene 6) increases EGFR signaling and leads to epidermal thickening (7).…”

“…2B). We previously reported that expression levels of Krt16 and Lce3a were increased in the paw skin of Slurp1 −/− mice, while levels of Krt24 and Lce1m expression were reduced (5). In the current study, we confirmed those findings, and we found no evidence that those gene-expression abnormalities were mitigated by homozygosity for the Egfr wa2 allele (Fig.…”