Decreased Profilaggrin Expression in Ichthyosis Vulgaris Is a Result of Selectively Impaired Posttranscriptional Control

Nirunsuksiri, Wilas; Presland, Richard B.; Brumbaugh, Steven; Dale, Beverly A.; Fleckman, Philip

doi:10.1074/jbc.270.2.871

Cited by 63 publications

(59 citation statements)

References 53 publications

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“…Mutations in the loricrin gene accompanying abnormal CE formation are responsible for Vohwinkel's syndrome, a palmoplantar hyperkeratosis with ainhum-like constrictions of the fingers (Maestrini et al 1996;Korge et al 1997), and for progressive symmetric erythrokeratoderma (PSEK), which is characterized by a similar phenotype with expanded erythematous hyperkeratotic plaques (IshidaYamamoto et al 1997). In addition, low levels of profilaggrin have been detected in ichthyosis vulgaris, a mild hyperkeratosis (Nirunsuksiri et al 1995), and coordinate overexpression of S100A7, S100A8, S100A9, SPRR1, and SPRR2 has been shown in chronic inflammatory and hyperproliferative psoriasis (Hardas et al 1996), in line with a psoriasis susceptibility locus within the 1q21 region (Capon et al 1999).…”

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confidence: 85%

Identification of Human Epidermal Differentiation Complex (EDC)-Encoded Genes by Subtractive Hybridization of Entire YACs to a Gridded Keratinocyte cDNA Library

Marenholz¹,

Zirra²,

Fischer³

et al. 2001

Genome Res.

104

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The epidermal differentiation complex (EDC) comprises a large number of genes that are of crucial importance for the maturation of the human epidermis. So far, 27 genes of 3 related families encoding structural as well as regulatory proteins have been mapped within a 2-Mb region on chromosome 1q21. Here we report on the identification of 10 additional EDC genes by a powerful subtractive hybridization method using entire YACs (950 e 2 and 986 e 10) to screen a gridded human keratinocyte cDNA library. Localization of the detected cDNA clones has been established on a long-range restriction map covering more than 5 Mb of this genomic region. The genes encode cytoskeletal tropomyosin TM30nm (TPM3), HS1-binding protein Hax-1 (HAX1), RNA-specific adenosine deaminase (ADAR1), the 34/67-kD laminin receptor (LAMRL6), and the 26S proteasome subunit p31 (PSMD8L), as well as five hitherto uncharacterized proteins (NICE-1, NICE-2, NICE-3, NICE-4, and NICE-5). The nucleotide sequences and putative ORFs of the EDC genes identified here revealed no homology with any of the established EDC gene families. Whereas database searches revealed that NICE-3, NICE-4, and NICE-5 were expressed in many tissues, no EST or gene-specific sequence was found for NICE-2. Expression of NICE-1 was up-regulated in differentiated keratinocytes, pointing to its relevance for the terminal differentiation of the epidermis. The newly identified EDC genes are likely to provide further insights into epidermal differentiation and they are potential candidates to be involved in skin diseases and carcinogenesis that are associated with this region of chromosome 1. Moreover, the extended integrated map of the EDC, including the polymorphic sequence tag site (STS) markers D1S1664, D1S2346, and D1S305, will serve as a valuable tool for linkage analyses.

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confidence: 85%

Identification of Human Epidermal Differentiation Complex (EDC)-Encoded Genes by Subtractive Hybridization of Entire YACs to a Gridded Keratinocyte cDNA Library

Marenholz¹,

Zirra²,

Fischer³

et al. 2001

Genome Res.

104

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“…Several strong lines of evidence had previously supported a causative role for filaggrin in ichthyosis vulgaris; these included loss of the granular layer (as assessed histologically), absence of immunohistochemical staining for filaggrin, reduced FLG mRNA levels and reduced or indeed absent filaggrin protein in the skin of individuals with ichthyosis vulgaris (Fleckman and Brumbaugh, 2002;Nirunsuksiri et al, 1995;Sybert et al, 1985). Despite these observations, previous attempts to sequence the FLG gene were hampered by the highly repetitive DNA sequence that is common to the individual filaggrin repeats, which severely limits the choice of suitable priming sites.…”

Section: Ichthyosis Vulgarismentioning

confidence: 99%

Filaggrin in the frontline: role in skin barrier function and disease

Sandilands

Sutherland

Irvine

et al. 2009

Journal of Cell Science

717

685

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Recently, loss-of-function mutations in FLG, the human gene encoding profilaggrin and filaggrin, have been identified as the cause of the common skin condition ichthyosis vulgaris (which is characterised by dry, scaly skin). These mutations, which are carried by up to 10% of people, also represent a strong genetic predisposing factor for atopic eczema, asthma and allergies. Profilaggrin is the major component of the keratohyalin granules within epidermal granular cells. During epidermal terminal differentiation, the ~400 kDa profilaggrin polyprotein is dephosphorylated and rapidly cleaved by serine proteases to form monomeric filaggrin (37 kDa), which binds to and condenses the keratin cytoskeleton and thereby contributes to the cell compaction process that is required for squame biogenesis. Within the squames, filaggrin is citrullinated, which promotes its unfolding and further degradation into hygroscopic amino acids, which constitute one element of natural moisturising factor. Loss of profilaggrin or filaggrin leads to a poorly formed stratum corneum (ichthyosis), which is also prone to water loss (xerosis). Recent human genetic studies strongly suggest that perturbation of skin barrier function as a result of reduction or complete loss of filaggrin expression leads to enhanced percutaneous transfer of allergens. Filaggrin is therefore in the frontline of defence, and protects the body from the entry of foreign environmental substances that can otherwise trigger aberrant immune responses.

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“…Perhaps the best evidence that these amino acids do play a role in normal epidermal flexibility and desquamation is the human skin disorder ichthyosis vulgaris (IV). This disorder is characterized phenotypically by dry, flaky skin and biochemically by reduced or absent profilaggrin expression (Sybert et al, 1985;Nirunsuksiri et al, 1995Nirunsuksiri et al, , 1998. The defect in IV appears to be specific to profilaggrin, since other markers of epidermal differentiation such as keratin 1 or loricrin are expressed normally (Nirunsuksiri et al, 1995).…”

Section: (B) Skin Disorders Associated With Keratin Mutationsmentioning

confidence: 99%

Epithelial Structural Proteins of the Skin and Oral Cavity: Function in Health and Disease

Presland

Dale

2000

Critical Reviews in Oral Biology & Medicine

Self Cite

349

328

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Epithelial tissues function to protect the organism from physical, chemical, and microbial damage and are essential for survival. To perform this role, epithelial keratinocytes undergo a well-defined differentiation program that results in the expression of structural proteins which maintain the integrity of epithelial tissues and function as a protective barrier. This review focuses on structural proteins of the epidermis and oral mucosa. Keratin proteins comprise the predominant cytoskeletal component of these epithelia. Keratin filaments are attached to the plasma membrane via desmosomes, and together these structural components form a threedimensional array within the cytoplasm of epithelial cells and tissues. Desmosomes contain two types of transmembrane proteins, the desmogleins and desmocollins, that are members of the cadherin family. The desmosomal cadherins are linked to the keratin cytoskeleton via several cytoplasmic plaque proteins, including desmoplakin and plakoglobin (-y-catenin). Epidermal and oral keratinocytes express additional differentiation markers, including filaggrin and trichohyalin, that associate with the keratin cytoskeleton during terminal differentiation, and proteins such as loricrin, small proline-rich proteins, and involucrin, that are cross-linked into the cornified envelope by transglutaminase enzymes. The importance of these cellular structures is highlighted by the large numbers of genetic and acquired (autoimmune) human disorders that involve mutations in, or autoantibodies to, keratins and desmosomal and cornified envelope proteins. While much progress has been made in the identification of the structural proteins and enzymes involved in epithelial differentiation, regulation of this process is less clear. Both calcium and retinoids influence epithelial differentiation by altering the transcription of target genes and by regulating activity of enzymes critical in epithelial differentiation, such as transglutaminases proteinases, and protein kinases. These studies have furthered our understanding of how epithelial tissue and cell integrity is maintained and provide a basis for the future treatment of skin and oral disorders by gene therapy and other novel therapeutics.

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Decreased Profilaggrin Expression in Ichthyosis Vulgaris Is a Result of Selectively Impaired Posttranscriptional Control

Cited by 63 publications

References 53 publications

Identification of Human Epidermal Differentiation Complex (EDC)-Encoded Genes by Subtractive Hybridization of Entire YACs to a Gridded Keratinocyte cDNA Library

Identification of Human Epidermal Differentiation Complex (EDC)-Encoded Genes by Subtractive Hybridization of Entire YACs to a Gridded Keratinocyte cDNA Library

Filaggrin in the frontline: role in skin barrier function and disease

Epithelial Structural Proteins of the Skin and Oral Cavity: Function in Health and Disease

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