Palmoplantar keratoderma in Slurp1/Slurp2 double-knockout mice

Allan, Christopher M.; Heizer, Patrick J.; Jung, Cris J.; Tu, Yiping; Tran, Deanna; Young, Lorraine; Fong, Loren G.; Jong, Pieter J. de; Beigneux, Anne P.; Young, Stephen G.

doi:10.1016/j.jdermsci.2017.08.014

Cited by 3 publications

(1 citation statement)

References 8 publications

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“…These mutations grossly impair the folding of the LU domain, preventing efficient secretion from cells [48]. Deletions of either SLURP-1 or SLURP-2 leads to a mal de Meleda -like phenotype in mice and the combined double deficiency causes a comparable disease severity, as presented by the individual single deficiencies, suggesting that SLURP-1 and SLURP-2 either act together or act sequentially in the same pathway [49,50,51]. SLURP-1 inhibits keratinocyte proliferation in vitro by 40%, presumably by antagonizing binding to the α7-nAChR with low nanomolar affinities [31], while SLURP-2 in contrast stimulates keratinocyte proliferation in vitro and presents a more promiscuous binding profile towards several AChRs [52].…”

Section: Mammalian Lu Domain Proteinsmentioning

confidence: 99%

Evolution and Medical Significance of LU Domain−Containing Proteins

Leth

Leth-Espensen

Kristensen

et al. 2019

IJMS

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Proteins containing Ly6/uPAR (LU) domains exhibit very diverse biological functions and have broad taxonomic distributions in eukaryotes. In general, they adopt a characteristic three-fingered folding topology with three long loops projecting from a disulfide-rich globular core. The majority of the members of this protein domain family contain only a single LU domain, which can be secreted, glycolipid anchored, or constitute the extracellular ligand binding domain of type-I membrane proteins. Nonetheless, a few proteins contain multiple LU domains, for example, the urokinase receptor uPAR, C4.4A, and Haldisin. In the current review, we will discuss evolutionary aspects of this protein domain family with special emphasis on variations in their consensus disulfide bond patterns. Furthermore, we will present selected cases where missense mutations in LU domain−containing proteins leads to dysfunctional proteins that are causally linked to genesis of human disease.

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Section: Mammalian Lu Domain Proteinsmentioning

confidence: 99%

Evolution and Medical Significance of LU Domain−Containing Proteins

Leth

Leth-Espensen

Kristensen

et al. 2019

IJMS

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Pain Hypersensitivity in SLURP1 and SLURP2 Knock-out Mouse Models of Hereditary Palmoplantar Keratoderma

Weinberg,

Kim,

Pang

et al. 2024

J. Neurosci.

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SLURP1 and SLURP2 are both small secreted members of the Ly6/u-PAR family of proteins and are highly expressed in keratinocytes. Loss of function mutations in SLURP1 lead to a rare autosomal recessive Palmoplantar Keratoderma (PPK), Mal de Meleda (MdM), which is characterized by diffuse, yellowish palmoplantar hyperkeratosis. Some individuals with MdM experience pain in conjunction with the hyperkeratosis that has been attributed to fissures or microbial superinfection within the affected skin. By comparison, other hereditary PPKs such as Pachyonychia congenita (PC) and Olmsted syndrome (OS) show prevalent pain in PPK lesions. Two mouse models of MdM, Slurp1 knockout and Slurp2X knockout, exhibit robust PPK in all four paws. However, whether the sensory experience of these animals including augmented pain sensitivity remains unexplored. In this study, we demonstrate that both models exhibit hypersensitivity to mechanical and thermal stimuli as well as spontaneous pain behaviors in males and females. Anatomical analysis revealed increased paw pad skin epidermal innervation and substantial alterations in palmoplantar skin immune composition in Slurp2X knockout mice. Primary sensory neurons innervating hind paw glabrous skin from Slurp2X knockout mice exhibit increased incidence of spontaneous activity and mechanical hypersensitivity both in vitro and in vivo. Thus, Slurp knockout mice exhibit polymodal PPK-associated pain that is associated with both immune alterations and neuronal hyperexcitability, and might therefore be useful for the identification of therapeutic targets to treat PPK-associated pain.Significance StatementPalmoplantar keratodermas (PPKs) are rare human skin disorders associated with thickening of the skin on the palms and soles. Pain is a common feature of some PPKs, yet the causes of PPK-associated pain are not understood. Here we show that two mouse models of one PPK, SLURP1 knockout mice and SLURP2 knockout mice, exhibit enhanced pain sensitivity and increased activity of pain-associated sensory neurons. These mouse lines will therefore be of value in defining causes of pain in PPKs and possibly developing improved therapies for that pain.

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Experimental Models for the Study of Hereditary Cornification Defects

et al. 2021

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Ichthyoses comprise a broad spectrum of keratinization disorders due to hereditary defects of cornification. Until now, mutations in more than 50 genes, mostly coding for structural proteins involved in epidermal barrier formation, have been identified as causes for different types of these keratinization disorders. However, due to the high heterogeneity and difficulties in the establishment of valid experimental models, research in this field remains challenging and translation of novel findings to clinical practice is difficult. In this review, we provide an overview of existing models to study hereditary cornification defects with focus on ichthyoses and palmoplantar keratodermas.

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Palmoplantar keratoderma in Slurp1/Slurp2 double-knockout mice

Cited by 3 publications

References 8 publications

Evolution and Medical Significance of LU Domain−Containing Proteins

Evolution and Medical Significance of LU Domain−Containing Proteins

Pain Hypersensitivity in SLURP1 and SLURP2 Knock-out Mouse Models of Hereditary Palmoplantar Keratoderma

Experimental Models for the Study of Hereditary Cornification Defects

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