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Richard B Presland - One of the best experts on this subject based on the ideXlab platform.
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crystal structure of human Profilaggrin s100 domain and identification of target proteins annexin ii stratifin and hsp27
Journal of Investigative Dermatology, 2015Co-Authors: Christopher G Bunick, Richard B Presland, Owen T Lawrence, David J Pearton, Leonard M Milstone, Thomas A SteitzAbstract:The fused-type S100 protein Profilaggrin and its proteolytic products including filaggrin are important in the formation of a normal epidermal barrier; however, the specific function of the S100 calcium-binding domain in Profilaggrin biology is poorly understood. To explore its molecular function, we determined a 2.2 A-resolution crystal structure of the N-terminal fused-type S100 domain of human Profilaggrin with bound calcium ions. The Profilaggrin S100 domain formed a stable dimer, which contained two hydrophobic pockets that provide a molecular interface for protein interactions. Biochemical and molecular approaches demonstrated that three proteins, annexin II/p36, stratifin/14-3-3 sigma, and heat shock protein 27, bind to the N-terminal domain of human Profilaggrin; one protein (stratifin) co-localized with Profilaggrin in the differentiating granular cell layer of human skin. Together, these findings suggest a model where the Profilaggrin N-terminus uses calcium-dependent and calcium-independent protein–protein interactions to regulate its involvement in keratinocyte terminal differentiation and incorporation into the cornified cell envelope.
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interaction of the Profilaggrin n terminal domain with loricrin in human cultured keratinocytes and epidermis
Journal of Investigative Dermatology, 2012Co-Authors: Kozo Yoneda, Owen T Lawrence, Toshio Demitsu, Yasuo Kubota, Toshitaka Nakagawa, Jessica Huard, Richard B PreslandAbstract:The relationship between the two coexpressed differentiation markers, Profilaggrin and loricrin, is not clear right now. In this study, we explored the interaction of Profilaggrin N-terminal domain (PND) with loricrin in keratinocytes and epidermis. Confocal immunofluorescence microscopic analysis of human epidermis showed that PND colocalized with loricrin. Loricrin nucleofected into HaCaT cells colocalized with PND in the nucleus and cytoplasm. The PND localizes to both the nucleus and cytoplasm of epidermal granular layer cells. Nucleofected PND also colocalized with keratin 10 (K10) in the nucleus and cytoplasm. Immunoelectron microscopic analysis of human epidermis confirmed the findings in nucleofected keratinocytes. Yeast two-hybrid assays showed that the B domain of human and mouse PND interacted with loricrin. The glutathione S-transferase (GST) pull-down analysis using recombinant GST-PND revealed that PND interacted with loricrin and K10. Knockdown of PND in an organotypic skin culture model caused loss of filaggrin expression and a reduction in both the size and number of keratohyalin granules, as well as markedly reduced expression of loricrin. Considering that expression of PND is closely linked to keratinocyte terminal differentiation, we conclude that PND interacts with loricrin and K10 in vivo and that these interactions are likely to be relevant for cornified envelope assembly and subsequent epidermal barrier formation.
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loss of normal Profilaggrin and filaggrin in flaky tail ft ft mice an animal model for the filaggrin deficient skin disease ichthyosis vulgaris
Journal of Investigative Dermatology, 2000Co-Authors: Richard B Presland, Philip Fleckman, Dawnalyn Boggess, Patrick S Lewis, Christopher M Hull, John P SundbergAbstract:Flaky tail (gene symbol ft) is an autosomal recessive mutation in mice that results in a dry, flaky skin, and annular tail and paw constrictions in the neonatal period. Previous studies demonstrated that the ft mutation maps to the central region of mouse chromosome 3, in the vicinity of the epidermal differentiation complex, a gene locus that includes many nonkeratin genes expressed in epidermis. In this study we report a detailed characterization of the flaky tail mouse. Affected homozygous ft/ft mice exhibit large, disorganized scales on tail and paw skin, marked attenuation of the epidermal granular layer, mild acanthosis, and orthokeratotic hyperkeratosis. Biochemical analysis demonstrated that ft/ft mice lacked normal high molecular Profilaggrin (≈ 500 kDa), and instead expressed a lower molecular weight form of Profilaggrin (220 kDa) that is not proteolytically processed to Profilaggrin intermediates or filaggrin. Mutant mice lacked the large, irregular F-type keratohyalin granules that contain Profilaggrin, and filaggrin was absent from the cornified layers of ft/ft epidermis. The expression of epidermal keratins was unchanged, whereas the cornified envelope proteins involucrin and loricrin were increased in ft/ft epidermis. Cultured ft/ft keratinocytes also synthesized reduced amounts of Profilaggrin mRNA and protein, demonstrating that the defect in Profilaggrin expression is intrinsic to epidermal cells. These findings demonstrate that flaky tail mice express an abnormal Profilaggrin polypeptide that does not form normal keratohyalin F-granules and is not proteolytically processed to filaggrin. We propose that the absence of filaggrin, and in particular the hygroscopic, filaggrin-derived amino acids that are thought to function in epidermal hydration, underlies the dry, scaly skin characteristic of ft/ft mice. This animal model provides a tool for understanding the role of filaggrin in normal epidermal function and may provide insight into the molecular basis of the filaggrin-deficient human skin disorder ichthyosis vulgaris.
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translocation of Profilaggrin n terminal domain into keratinocyte nuclei with fragmented dna in normal human skin and loricrin keratoderma
Laboratory Investigation, 1998Co-Authors: Akemi Ishidayamamoto, Beverly A Dale, Hidetoshi Takahashi, Richard B Presland, Hajime IizukaAbstract:The terminal differentiation of epidermal keratinocytes from the granular to enucleated cornified layer involves drastic changes both in morphology and biochemistry. Profilaggrin is a keratinocyte-specific phosphoprotein expressed in the granular layer. Although keratinization has been regarded as a specialized form of apoptosis or programmed cell death, the mechanism for this cellular transition at the molecular level is not yet well understood. In this study, we used light and electron microscopic immunohistochemistry to investigate the localization of the Profilaggrin domains during this process. Antibodies specific for the amino-terminal domains of Profilaggrin showed localization in keratohyalin granules in the granular cells, but stained the nucleus in transition cells. In contrast, an antibody to filaggrin domains stained the cytoplasm in the transition cells. Nuclei that were positive to amino-terminal profi;aggrin contained fragmented DNA, characteristic of apoptosis. In the epidermis of patients with progressive symmetric erythrokeratoderma carrying a mutation in the loricrin gene (loricrin keratoderma), the Profilaggrin amino-terminal domains were packed within apoptotic nuclei together with loricrin aggregates and this persisted up to the parakeratotic superficial layer. The present study indicates that the amino-terminal Profilaggrin domains are cleaved from the filaggrin repeats and transiently localized to the apoptotic nuclei just before the formation of enucleated stratum corneum in normal epidermis. This suggests a significant role for the Profilaggrin amino-terminus in nuclear events associated with keratinocyte terminal differentiation. Disrupted apoptosis found in loricrin keratoderma might explain the marked parakeratotic hyperkeratosis characteristic of this disease.
Philip Fleckman - One of the best experts on this subject based on the ideXlab platform.
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mapping of the associated phenotype of an absent granular layer in ichthyosis vulgaris to the epidermal differentiation complex on chromosome 1
Experimental Dermatology, 2002Co-Authors: John G Compton, Kay A Johnston, John J Digiovanna, Philip Fleckman, Sherri J BaleAbstract:: Ichthyosis vulgaris (IV) is a mild to severe scaling disorder of uncertain etiology estimated to affect as many as 1 : 250 in the population. Family studies have shown that in many cases IV follows an autosomal dominant inheritance pattern, but gene mapping studies have not been reported. To investigate the genetic basis for inherited IV, we have performed gene linkage studies in two multigenerational families where affected individuals have clinical features of IV but distinct histological features. The epidermis in this disorder characteristically displays non-specific orthohyperkeratosis. Notably, a subset of IV patients with a reduced or absent granular epidermal layer (AGL) have been reported, and decreased filaggrin levels have been described in others. The prominent role of Profilaggrin in human keratohyalin suggests that defects in the gene for Profilaggrin (FLG), its processing of profillagrin to filaggrin, or a gene involved in Profilaggrin regulation may underlie or modify the pathology in IV. Family 1 had seven individuals with IV, severe heat intolerance and epidermis with 1-3 granular layers (consistent with normal epidermal histology). Ichthyosis vulgaris in this family did not segregate with FLG or other genes in the epidermal differentiation complex. In contrast, five of the six IV patients in Family 2, all siblings, had epidermis with no granular layer. Significant evidence was obtained for linkage of IV with the associated AGL phenotype to the epidermal differentiation complex (which includes FLG) assuming either a recessive (max Lod 3.4) or dominant (max Lod 3.6) inheritance model. Sequence analysis of FLG did not reveal a mutation in the amino or carboxyl terminal portions of the coding sequence adjacent to filaggrin repeats. The AGL may represent an endophenotype for IV, and the presence of a modifier of IV pathology at this locus is discussed.
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absence of the granular layer and keratohyalin define a morphologically distinct subset of individuals with ichthyosis vulgaris
Experimental Dermatology, 2002Co-Authors: Philip Fleckman, Steve BrumbaughAbstract:: The clinical diagnosis of ichthyosis vulgaris (IV) can be difficult. Abnormalities in the granular layer and the ultrastructure of keratohyalin granules (KHG) suggest that morphology may be helpful. To clarify morphologic findings in IV, 41 clinically affected individuals and 21 unaffected family members or age- and sex-matched controls were studied by light microscopy. In these, the granular layer was totally absent in approximately 50% of affected individuals, while present in all controls. Forty-seven individuals in the light microscopy group were also studied by electron microscopy. Keratohyalin granules were absent in all affected individuals lacking the granular layer by light microscopy. Clinical severity usually correlated with the lack of a granular layer and KHG. Absence of the granular layer was consistent in different anatomic sites and in serial biopsies taken over a 1–3-year period. In a subset of clinically affected, unrelated subjects with moderate to severe involvement, four out of 11 (36%) had similar findings. Keratinocytes cultured from affected individuals with no KHG expressed virtually no detectable Profilaggrin protein in vitro. The data suggest that a subset of individuals with moderate to severe IV have a consistently absent granular layer and KHG. Absence of the granular layer and lack of KHG correlated almost perfectly; thus light microscopy offers a convenient means of identifying this subtype of IV. However, both morphologic types of IV were observed within single families. Therefore, the relationship between granular layer abnormalities and IV is complex and requires the study of more affected families. One interpretation of the data is that IV is a multigenic disorder in which one of the genes alters Profilaggrin expression. We propose this clinical and histologic phenotype as useful for identifying the gene(s) involved and also for determining whether it represents a modifier or a major locus of the disorder.
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loss of normal Profilaggrin and filaggrin in flaky tail ft ft mice an animal model for the filaggrin deficient skin disease ichthyosis vulgaris
Journal of Investigative Dermatology, 2000Co-Authors: Richard B Presland, Philip Fleckman, Dawnalyn Boggess, Patrick S Lewis, Christopher M Hull, John P SundbergAbstract:Flaky tail (gene symbol ft) is an autosomal recessive mutation in mice that results in a dry, flaky skin, and annular tail and paw constrictions in the neonatal period. Previous studies demonstrated that the ft mutation maps to the central region of mouse chromosome 3, in the vicinity of the epidermal differentiation complex, a gene locus that includes many nonkeratin genes expressed in epidermis. In this study we report a detailed characterization of the flaky tail mouse. Affected homozygous ft/ft mice exhibit large, disorganized scales on tail and paw skin, marked attenuation of the epidermal granular layer, mild acanthosis, and orthokeratotic hyperkeratosis. Biochemical analysis demonstrated that ft/ft mice lacked normal high molecular Profilaggrin (≈ 500 kDa), and instead expressed a lower molecular weight form of Profilaggrin (220 kDa) that is not proteolytically processed to Profilaggrin intermediates or filaggrin. Mutant mice lacked the large, irregular F-type keratohyalin granules that contain Profilaggrin, and filaggrin was absent from the cornified layers of ft/ft epidermis. The expression of epidermal keratins was unchanged, whereas the cornified envelope proteins involucrin and loricrin were increased in ft/ft epidermis. Cultured ft/ft keratinocytes also synthesized reduced amounts of Profilaggrin mRNA and protein, demonstrating that the defect in Profilaggrin expression is intrinsic to epidermal cells. These findings demonstrate that flaky tail mice express an abnormal Profilaggrin polypeptide that does not form normal keratohyalin F-granules and is not proteolytically processed to filaggrin. We propose that the absence of filaggrin, and in particular the hygroscopic, filaggrin-derived amino acids that are thought to function in epidermal hydration, underlies the dry, scaly skin characteristic of ft/ft mice. This animal model provides a tool for understanding the role of filaggrin in normal epidermal function and may provide insight into the molecular basis of the filaggrin-deficient human skin disorder ichthyosis vulgaris.
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reduced stability and bi allelic coequal expression of Profilaggrin mrna in keratinocytes cultured from subjects with ichthyosis vulgaris
Journal of Investigative Dermatology, 1998Co-Authors: Wilas Nirunsuksiri, Shehui Zhang, Philip FleckmanAbstract:Ichthyosis vulgaris (IV) is an inherited scaling skin disorder in which expression of Profilaggrin is reduced. Previous studies have indicated that the reduction is caused by defective post-transcriptional control of gene expression. Here we present evidence that Profilaggrin mRNA in keratinocytes cultured from subjects with IV is intrinsically unstable and has a shorter half-life compared with that in normal cells. When IV-affected keratinocytes were treated with the protein synthesis inhibitor cycloheximide, the steady-state level of Profilaggrin mRNA was increased due to stabilization of the transcript. In addition, the number of filaggrin repeats within the Profilaggrin gene was studied. The number of filaggrin repeats (10–12) in individuals with IV did not differ from that of unaffected subjects. Expression of the gene was bi-allelic and coequal in both control and affected individuals. Our results suggest a model in which a labile ribonuclease and a stabilizing factor may modulate the Profilaggrin mRNA steady-state level in normal cells, whereas the stabilizing factor may be absent or functionally inactive in IV-affected keratinocytes.
John P Sundberg - One of the best experts on this subject based on the ideXlab platform.
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loss of normal Profilaggrin and filaggrin in flaky tail ft ft mice an animal model for the filaggrin deficient skin disease ichthyosis vulgaris
Journal of Investigative Dermatology, 2000Co-Authors: Richard B Presland, Philip Fleckman, Dawnalyn Boggess, Patrick S Lewis, Christopher M Hull, John P SundbergAbstract:Flaky tail (gene symbol ft) is an autosomal recessive mutation in mice that results in a dry, flaky skin, and annular tail and paw constrictions in the neonatal period. Previous studies demonstrated that the ft mutation maps to the central region of mouse chromosome 3, in the vicinity of the epidermal differentiation complex, a gene locus that includes many nonkeratin genes expressed in epidermis. In this study we report a detailed characterization of the flaky tail mouse. Affected homozygous ft/ft mice exhibit large, disorganized scales on tail and paw skin, marked attenuation of the epidermal granular layer, mild acanthosis, and orthokeratotic hyperkeratosis. Biochemical analysis demonstrated that ft/ft mice lacked normal high molecular Profilaggrin (≈ 500 kDa), and instead expressed a lower molecular weight form of Profilaggrin (220 kDa) that is not proteolytically processed to Profilaggrin intermediates or filaggrin. Mutant mice lacked the large, irregular F-type keratohyalin granules that contain Profilaggrin, and filaggrin was absent from the cornified layers of ft/ft epidermis. The expression of epidermal keratins was unchanged, whereas the cornified envelope proteins involucrin and loricrin were increased in ft/ft epidermis. Cultured ft/ft keratinocytes also synthesized reduced amounts of Profilaggrin mRNA and protein, demonstrating that the defect in Profilaggrin expression is intrinsic to epidermal cells. These findings demonstrate that flaky tail mice express an abnormal Profilaggrin polypeptide that does not form normal keratohyalin F-granules and is not proteolytically processed to filaggrin. We propose that the absence of filaggrin, and in particular the hygroscopic, filaggrin-derived amino acids that are thought to function in epidermal hydration, underlies the dry, scaly skin characteristic of ft/ft mice. This animal model provides a tool for understanding the role of filaggrin in normal epidermal function and may provide insight into the molecular basis of the filaggrin-deficient human skin disorder ichthyosis vulgaris.
Hans Christian Hennies - One of the best experts on this subject based on the ideXlab platform.
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ichthyosis follicular atrophoderma and hypotrichosis caused by mutations in st14 is associated with impaired Profilaggrin processing
Journal of Investigative Dermatology, 2009Co-Authors: Thomas Alef, Ingrid Hausser, Gilles G. Lestringant, Serena Torres, Dieter Metze, Umit Tursen, Hans Christian HenniesAbstract:Congenital ichthyosis encompasses a heterogeneous group of disorders of cornification. Isolated forms and syndromic ichthyosis can be differentiated. We have analyzed two consanguineous families from the United Arab Emirates and Turkey with an autosomal recessive syndrome of diffuse congenital ichthyosis, patchy follicular atrophoderma, generalized and diffuse nonscarring hypotrichosis, marked hypohidrosis, and woolly hair (OMIM 602400). By genome-wide analysis, we found a homozygous interval on chromosome 11q24–q25 and obtained a LOD score of 4.0 at D11S910. We identified a homozygous splice-site mutation in the Arab patients and a frame-shift deletion in the Turkish patient in the gene suppression of tumorigenicity-14 (ST14). The product of ST14, matriptase, is a type II transmembrane serine protease synthesized in most human epithelia. Two missense mutations in ST14 were recently described in patients with a phenotype of ichthyosis and hypotrichosis, indicating diverse activities of matriptase in the epidermis and hair follicles. Here we have further demonstrated the loss of matriptase in differentiated patient keratinocytes, reduced proteolytic activation of prostasin, and disturbed processing of Profilaggrin. As filaggrin monomers play a pivotal role in epidermal barrier formation, these findings reveal the link between congenital disorders of keratinization and filaggrin processing in the human skin.
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ichthyosis follicular atrophoderma and hypotrichosis caused by mutations in st14 is associated with impaired Profilaggrin processing
Journal of Investigative Dermatology, 2009Co-Authors: Thomas Alef, Ingrid Hausser, Gilles G. Lestringant, Serena Torres, Dieter Metze, Umit Tursen, Hans Christian HenniesAbstract:Congenital ichthyosis encompasses a heterogeneous group of disorders of cornification. Isolated forms and syndromic ichthyosis can be differentiated. We have analyzed two consanguineous families from the United Arab Emirates and Turkey with an autosomal recessive syndrome of diffuse congenital ichthyosis, patchy follicular atrophoderma, generalized and diffuse nonscarring hypotrichosis, marked hypohidrosis, and woolly hair (OMIM 602400). By genome-wide analysis, we found a homozygous interval on chromosome 11q24–q25 and obtained a LOD score of 4.0 at D11S910. We identified a homozygous splice-site mutation in the Arab patients and a frame-shift deletion in the Turkish patient in the gene suppression of tumorigenicity-14 (ST14). The product of ST14, matriptase, is a type II transmembrane serine protease synthesized in most human epithelia. Two missense mutations in ST14 were recently described in patients with a phenotype of ichthyosis and hypotrichosis, indicating diverse activities of matriptase in the epidermis and hair follicles. Here we have further demonstrated the loss of matriptase in differentiated patient keratinocytes, reduced proteolytic activation of prostasin, and disturbed processing of Profilaggrin. As filaggrin monomers play a pivotal role in epidermal barrier formation, these findings reveal the link between congenital disorders of keratinization and filaggrin processing in the human skin.
John A Mcgrath - One of the best experts on this subject based on the ideXlab platform.
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Profilaggrin dry skin and atopic dermatitis risk size matters
Journal of Investigative Dermatology, 2012Co-Authors: John A McgrathAbstract:Mutations in the FLG gene, which encodes Profilaggrin, are known to be a major risk factor for atopic dermatitis as well as other atopic diseases and systemic allergies. New research, however, shows that intragenic copy number variation within FLG also represents an independent risk factor for atopic dermatitis. The new findings indicate that upregulating FLG protein levels by 5–10% may have clinical utility in improving the management of many patients with dry skin and atopy.
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the filaggrin story novel insights into skin barrier function and disease
Trends in Molecular Medicine, 2008Co-Authors: John A Mcgrath, Jouni UittoAbstract:Recent reports have uncovered the key role of the protein filaggrin in maintaining an effective skin barrier against the external environment. Loss-of-function mutations in the Profilaggrin gene (FLG) are common and are present in up to 10% of the population. These mutations are the cause of the semi-dominant skin-scaling disorder ichthyosis vulgaris and are a major risk factor for the development of atopic dermatitis. The discovery of these mutations also provides new data concerning the genetics of atopic asthma as well as intriguing insight into disease mechanisms of systemic allergies involving antigen exposure in skin with defective barrier function. Collectively, these novel findings have significant implications for the classification and future clinical management of patients with atopic and allergic diseases.
