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Leslie Robinsonbostom - One of the best experts on this subject based on the ideXlab platform.
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histopathologic characterization of Epidermolytic Hyperkeratosis a systematic review of histology from the national registry for ichthyosis and related skin disorders
Journal of The American Academy of Dermatology, 2008Co-Authors: Rustin Ross, J J Digiovanna, Laura Capaldi, Zsolt B Argenyi, Philip Fleckman, Leslie RobinsonbostomAbstract:Background The clinical condition generalized Epidermolytic Hyperkeratosis, also known as bullous congenital ichthyosiform erythroderma, is an autosomal dominant disorder and presents as a bullous disease of the newborn followed by an ichthyotic skin disorder throughout life. Clinical Epidermolytic Hyperkeratosis (cEHK) has characteristic histopathologic findings. Mosaic cEHK, which occurs without a family history, is a sporadic condition that clinically resembles epidermal nevi but demonstrates histopathologic findings similar to the generalized disorder; when a postzygotic mutation involves the germ line, the disease can occur in subsequent generations as generalized cEHK. Ichthyosis bullosa of Siemens (IBS) is similar histopathogically, but is clinically distinct from generalized cEHK, presenting with more superficial bullae. Objectives It is well established that the clinical diagnoses generalized cEHK, mosaic cEHK, and IBS have similar histopathologic findings of epidermolysis with Hyperkeratosis. We sought (1) to characterize the spectrum of histopathologic features and (2) to assess whether there were histopathologic differences between these clinically distinct disorders. Methods One hundred seventeen skin biopsy slides from the National Registry for Ichthyosis and Related Skin Disorders were reviewed, with those reviewers blinded to clinical information. All slides were systematically evaluated for a variety of features, including differences in the pattern of the epidermolysis and Hyperkeratosis. Clinical predictions of whether the biopsy specimen was obtained from patients with generalized cEHK, mosaic cEHK, or IBS were made on the basis of histologic pattern of the epidermolysis and Hyperkeratosis. Results Eighteen of the 117 slides revealed features sufficient to make a histologic diagnosis of Epidermolytic Hyperkeratosis (hEHK). One additional slide, for which a definitive histologic diagnosis was not possible, had features of both hEHK and acantholytic dyskeratosis. Two distinct patterns of the histopathologic changes were observed within the 18 slides diagnostic of hEHK: (1) continuous involvement of the entire horizontal epidermis and (2) focal involvement revealing skip areas of normal-appearing epidermis along the horizontal epidermis. Upon clinical correlation, all 12 of the slides with continuous involvement were from patients with generalized cEHK. One slide was from acral skin and had continuous involvement; this was from a patient with Vorner's palmoplantar keratoderma. Of the remaining 5 slides with focal involvement, two patterns were observed: focal involvement of both granular and spinous layers and focal involvement of only the granular layer. The 3 slides with focal involvement of the granular and spinous layers were from patients with mosaic cEHK. Of the two slides with focal involvement confined to the granular layer, one was from a patient with IBS and the other from a patient with generalized cEHK. Limitation The sample pool is biased by who was enrolled in the Registry and therefore may not represent the full spectrum of the disease. Conclusion The pattern of histologic involvement may be a useful predictor of the clinical phenotype of cEHK.
J J Digiovanna - One of the best experts on this subject based on the ideXlab platform.
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histopathologic characterization of Epidermolytic Hyperkeratosis a systematic review of histology from the national registry for ichthyosis and related skin disorders
Journal of The American Academy of Dermatology, 2008Co-Authors: Rustin Ross, J J Digiovanna, Laura Capaldi, Zsolt B Argenyi, Philip Fleckman, Leslie RobinsonbostomAbstract:Background The clinical condition generalized Epidermolytic Hyperkeratosis, also known as bullous congenital ichthyosiform erythroderma, is an autosomal dominant disorder and presents as a bullous disease of the newborn followed by an ichthyotic skin disorder throughout life. Clinical Epidermolytic Hyperkeratosis (cEHK) has characteristic histopathologic findings. Mosaic cEHK, which occurs without a family history, is a sporadic condition that clinically resembles epidermal nevi but demonstrates histopathologic findings similar to the generalized disorder; when a postzygotic mutation involves the germ line, the disease can occur in subsequent generations as generalized cEHK. Ichthyosis bullosa of Siemens (IBS) is similar histopathogically, but is clinically distinct from generalized cEHK, presenting with more superficial bullae. Objectives It is well established that the clinical diagnoses generalized cEHK, mosaic cEHK, and IBS have similar histopathologic findings of epidermolysis with Hyperkeratosis. We sought (1) to characterize the spectrum of histopathologic features and (2) to assess whether there were histopathologic differences between these clinically distinct disorders. Methods One hundred seventeen skin biopsy slides from the National Registry for Ichthyosis and Related Skin Disorders were reviewed, with those reviewers blinded to clinical information. All slides were systematically evaluated for a variety of features, including differences in the pattern of the epidermolysis and Hyperkeratosis. Clinical predictions of whether the biopsy specimen was obtained from patients with generalized cEHK, mosaic cEHK, or IBS were made on the basis of histologic pattern of the epidermolysis and Hyperkeratosis. Results Eighteen of the 117 slides revealed features sufficient to make a histologic diagnosis of Epidermolytic Hyperkeratosis (hEHK). One additional slide, for which a definitive histologic diagnosis was not possible, had features of both hEHK and acantholytic dyskeratosis. Two distinct patterns of the histopathologic changes were observed within the 18 slides diagnostic of hEHK: (1) continuous involvement of the entire horizontal epidermis and (2) focal involvement revealing skip areas of normal-appearing epidermis along the horizontal epidermis. Upon clinical correlation, all 12 of the slides with continuous involvement were from patients with generalized cEHK. One slide was from acral skin and had continuous involvement; this was from a patient with Vorner's palmoplantar keratoderma. Of the remaining 5 slides with focal involvement, two patterns were observed: focal involvement of both granular and spinous layers and focal involvement of only the granular layer. The 3 slides with focal involvement of the granular and spinous layers were from patients with mosaic cEHK. Of the two slides with focal involvement confined to the granular layer, one was from a patient with IBS and the other from a patient with generalized cEHK. Limitation The sample pool is biased by who was enrolled in the Registry and therefore may not represent the full spectrum of the disease. Conclusion The pattern of histologic involvement may be a useful predictor of the clinical phenotype of cEHK.
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Histopathologic Characterization of Epidermolytic Hyperkeratosis: A Systematic Review of Histology from the National Registry for Ichthyosis and Related Skin Disorders
Journal of the American Academy of Dermatology, 2008Co-Authors: Rustin Ross, J J Digiovanna, Laura Capaldi, Zsolt B Argenyi, Philip Fleckman, Leslie Robinson-bostomAbstract:Background The clinical condition generalized Epidermolytic Hyperkeratosis, also known as bullous congenital ichthyosiform erythroderma, is an autosomal dominant disorder and presents as a bullous disease of the newborn followed by an ichthyotic skin disorder throughout life. Clinical Epidermolytic Hyperkeratosis (cEHK) has characteristic histopathologic findings. Mosaic cEHK, which occurs without a family history, is a sporadic condition that clinically resembles epidermal nevi but demonstrates histopathologic findings similar to the generalized disorder; when a postzygotic mutation involves the germ line, the disease can occur in subsequent generations as generalized cEHK. Ichthyosis bullosa of Siemens (IBS) is similar histopathogically, but is clinically distinct from generalized cEHK, presenting with more superficial bullae. Objectives It is well established that the clinical diagnoses generalized cEHK, mosaic cEHK, and IBS have similar histopathologic findings of epidermolysis with Hyperkeratosis. We sought (1) to characterize the spectrum of histopathologic features and (2) to assess whether there were histopathologic differences between these clinically distinct disorders. Methods One hundred seventeen skin biopsy slides from the National Registry for Ichthyosis and Related Skin Disorders were reviewed, with those reviewers blinded to clinical information. All slides were systematically evaluated for a variety of features, including differences in the pattern of the epidermolysis and Hyperkeratosis. Clinical predictions of whether the biopsy specimen was obtained from patients with generalized cEHK, mosaic cEHK, or IBS were made on the basis of histologic pattern of the epidermolysis and Hyperkeratosis. Results Eighteen of the 117 slides revealed features sufficient to make a histologic diagnosis of Epidermolytic Hyperkeratosis (hEHK). One additional slide, for which a definitive histologic diagnosis was not possible, had features of both hEHK and acantholytic dyskeratosis. Two distinct patterns of the histopathologic changes were observed within the 18 slides diagnostic of hEHK: (1) continuous involvement of the entire horizontal epidermis and (2) focal involvement revealing skip areas of normal-appearing epidermis along the horizontal epidermis. Upon clinical correlation, all 12 of the slides with continuous involvement were from patients with generalized cEHK. One slide was from acral skin and had continuous involvement; this was from a patient with Vorner's palmoplantar keratoderma. Of the remaining 5 slides with focal involvement, two patterns were observed: focal involvement of both granular and spinous layers and focal involvement of only the granular layer. The 3 slides with focal involvement of the granular and spinous layers were from patients with mosaic cEHK. Of the two slides with focal involvement confined to the granular layer, one was from a patient with IBS and the other from a patient with generalized cEHK. Limitation The sample pool is biased by who was enrolled in the Registry and therefore may not represent the full spectrum of the disease. Conclusion The pattern of histologic involvement may be a useful predictor of the clinical phenotype of cEHK.
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Clinical heterogeneity in Epidermolytic Hyperkeratosis.
Archives of Dermatology, 1994Co-Authors: J J Digiovanna, S J BaleAbstract:Background and Design: Epidermolytic Hyperkeratosis (EHK) is a rare autosomal dominant disorder of cornification. While different clinical presentations of EHK have been described, the distinctions have not been clear. We have examined 52 patients with EHK from 21 families in an effort to define and characterize the specific clinical features of this disorder. Results: We found that several features were useful for separating patients with EHK into clinical groups. The most distinctive characteristic was presence vs absence of severe palmoplantar Hyperkeratosis. Twenty-nine patients in six families had this finding and were grouped into ''PS types'' (those with severe palm/sole Hyperkeratosis). The remaining 23 patients (from 15 families) were classified as ''NPS types'' (those without severe palm/ sole Hyperkeratosis). We identified three distinct PS types and three distinct NPS types. The classification was always found to be consistent in all affected family members. In those families in which mutations were defined, keratin 1 mutations were identified in the PS types and keratin 10 mutations in the NPS types. Conclusions: We were able to classify our cohort of 52 patients with EHK from 21 families into distinct types. There was a correlation between presence or absence of severe palm/sole Hyperkeratosis and the specific keratin involved. (Arch Dermatol. 1994;130:1026-1035)
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Epidermolytic Hyperkeratosis: Applied Molecular Genetics
Journal of Investigative Dermatology, 1994Co-Authors: J J Digiovanna, S J BaleAbstract:Epidermolytic Hyperkeratosis is an autosomal dominant ichthyosis characterized by blistering, especially at birth and during childhood, and Hyperkeratosis. Epidermolytic Hyperkeratosis presents striking clinical heterogeneity, particularly between families. Several avenues of research have implicated an abnormality of epidermal differentiation in the pathogenesis of this disease. In a three-generation family with 20 affected individuals, we tested a variety of candidate loci and identified linkage to the type II keratin region on chromosome 12. Further investigation revealed a mutation in the H1 subdomain of the keratin 1 gene as the cause of EHK in this family. Because keratin 10 is the co-expressed partner of keratin 1, it was not surprising when abnormalities in keratin 10 were found in other families with EHK. We have examined 52 patients from 21 families and have identified at least six clinical phenotypes. The most useful distinguishing feature was the presence or absence of severe hyper keratosis of the palms and soles. We and others are continuing to search for and characterize mutations in keratin 1 and 10 in patients with Epidermolytic Hyperkeratosis. Correlation of the clinical disease types with the specific mutations should lead to a better understanding of the relationship between keratin structure and function in normal and diseased epidermis.
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Mutations in the H1 and 1A Domains in the Keratin 1 Gene in Epidermolytic Hyperkeratosis
Journal of Investigative Dermatology, 1994Co-Authors: Jun-mo Yang, S J Bale, J J Digiovanna, Peter M. Steinert, Constantin C. Chipev, Lyuben N. Marekov, John G. ComptonAbstract:In the autosomal dominant disorder Epidermolytic Hyperkeratosis, the structural integrity of the keratin intermediate filaments is altered in the suprabasal layers of the epidermis. We and others have used genetic linkage studies and mutation analysis to establish that single amino acid substitutions in either the keratin 1 or keratin 10 chains can cause Epidermolytic Hyperkeratosis. However, a larger database of mutations is required to better understand the relationship between specific mutations in these keratin chains and their effect on keratin filament structure. A larger database will also provide a catalog that may be useful for genetic counseling purposes. In this paper, we report the identification of three new mutations of the keratin 1 chain of Epidermolytic Hyperkeratosis probands in highly conserved residues in the H1 or beginning of the 1A rod domain segments. These correspond to regions involved in molecular overlaps between neighboring molecules in keratin filaments. Using an in vitro assay, synthetic peptides bearing these substitutions show diminished capacity to disassemble preformed filaments in vitro in comparison to the wild type peptides. Moreover, analyses of all mutations in Epidermolytic Hyperkeratosis known to date demonstrate remarkable clustering in the molecular overlap region. We conclude that non-conservative substitutions in the overlap region are likely to interfere with normal keratin filament structure and function, leading to pathology.
S J Bale - One of the best experts on this subject based on the ideXlab platform.
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Clinical heterogeneity in Epidermolytic Hyperkeratosis.
Archives of Dermatology, 1994Co-Authors: J J Digiovanna, S J BaleAbstract:Background and Design: Epidermolytic Hyperkeratosis (EHK) is a rare autosomal dominant disorder of cornification. While different clinical presentations of EHK have been described, the distinctions have not been clear. We have examined 52 patients with EHK from 21 families in an effort to define and characterize the specific clinical features of this disorder. Results: We found that several features were useful for separating patients with EHK into clinical groups. The most distinctive characteristic was presence vs absence of severe palmoplantar Hyperkeratosis. Twenty-nine patients in six families had this finding and were grouped into ''PS types'' (those with severe palm/sole Hyperkeratosis). The remaining 23 patients (from 15 families) were classified as ''NPS types'' (those without severe palm/ sole Hyperkeratosis). We identified three distinct PS types and three distinct NPS types. The classification was always found to be consistent in all affected family members. In those families in which mutations were defined, keratin 1 mutations were identified in the PS types and keratin 10 mutations in the NPS types. Conclusions: We were able to classify our cohort of 52 patients with EHK from 21 families into distinct types. There was a correlation between presence or absence of severe palm/sole Hyperkeratosis and the specific keratin involved. (Arch Dermatol. 1994;130:1026-1035)
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Epidermolytic Hyperkeratosis: Applied Molecular Genetics
Journal of Investigative Dermatology, 1994Co-Authors: J J Digiovanna, S J BaleAbstract:Epidermolytic Hyperkeratosis is an autosomal dominant ichthyosis characterized by blistering, especially at birth and during childhood, and Hyperkeratosis. Epidermolytic Hyperkeratosis presents striking clinical heterogeneity, particularly between families. Several avenues of research have implicated an abnormality of epidermal differentiation in the pathogenesis of this disease. In a three-generation family with 20 affected individuals, we tested a variety of candidate loci and identified linkage to the type II keratin region on chromosome 12. Further investigation revealed a mutation in the H1 subdomain of the keratin 1 gene as the cause of EHK in this family. Because keratin 10 is the co-expressed partner of keratin 1, it was not surprising when abnormalities in keratin 10 were found in other families with EHK. We have examined 52 patients from 21 families and have identified at least six clinical phenotypes. The most useful distinguishing feature was the presence or absence of severe hyper keratosis of the palms and soles. We and others are continuing to search for and characterize mutations in keratin 1 and 10 in patients with Epidermolytic Hyperkeratosis. Correlation of the clinical disease types with the specific mutations should lead to a better understanding of the relationship between keratin structure and function in normal and diseased epidermis.
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Mutations in the H1 and 1A Domains in the Keratin 1 Gene in Epidermolytic Hyperkeratosis
Journal of Investigative Dermatology, 1994Co-Authors: Jun-mo Yang, S J Bale, J J Digiovanna, Peter M. Steinert, Constantin C. Chipev, Lyuben N. Marekov, John G. ComptonAbstract:In the autosomal dominant disorder Epidermolytic Hyperkeratosis, the structural integrity of the keratin intermediate filaments is altered in the suprabasal layers of the epidermis. We and others have used genetic linkage studies and mutation analysis to establish that single amino acid substitutions in either the keratin 1 or keratin 10 chains can cause Epidermolytic Hyperkeratosis. However, a larger database of mutations is required to better understand the relationship between specific mutations in these keratin chains and their effect on keratin filament structure. A larger database will also provide a catalog that may be useful for genetic counseling purposes. In this paper, we report the identification of three new mutations of the keratin 1 chain of Epidermolytic Hyperkeratosis probands in highly conserved residues in the H1 or beginning of the 1A rod domain segments. These correspond to regions involved in molecular overlaps between neighboring molecules in keratin filaments. Using an in vitro assay, synthetic peptides bearing these substitutions show diminished capacity to disassemble preformed filaments in vitro in comparison to the wild type peptides. Moreover, analyses of all mutations in Epidermolytic Hyperkeratosis known to date demonstrate remarkable clustering in the molecular overlap region. We conclude that non-conservative substitutions in the overlap region are likely to interfere with normal keratin filament structure and function, leading to pathology.
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Epidermolytic Hyperkeratosis.
Seminars in dermatology, 1993Co-Authors: S J Bale, J G Compton, J J DigiovannaAbstract:Epidermolytic Hyperkeratosis (EHK) is a congenital autosomal dominant ichthyosis. The disorder is characterized by blistering, especially at birth and during childhood, and Hyperkeratosis. EHK presents striking clinical heterogeneity, particularly regarding extent of body surface involvement, quality of scale, presence or absence of erythroderma, and palmar/plantar involvement. Histological examination of hematoxylin-eosin stained sections of EHK skin show a tremendously thickened stratum corneum and vacuolar degeneration of the upper epidermis, leading to the term "Epidermolytic Hyperkeratosis". Genetic studies have revealed that defects in either keratin 1 or keratin 10 are responsible for the disorder in several patients, and provide a means for prenatal diagnosis in at-risk pregnancies in these families. An understanding of the relationship of keratin structure to its function in vivo in human epidermis may lead to the development of novel therapies for EHK.
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Linkage of Epidermolytic Hyperkeratosis to the type II keratin gene cluster on chromosome 12q.
Nature Genetics, 1992Co-Authors: John G. Compton, J J Digiovanna, Sandra K. Santucci, Kathleen S. Kearns, Christopher I. Amos, Donita L. Abangan, Bernhard P. Korge, O. Wesley Mcbride, Peter M. Steinert, S J BaleAbstract:Linkage of Epidermolytic Hyperkeratosis to the type II keratin gene cluster on chromosome 12q
Dennis R Roop - One of the best experts on this subject based on the ideXlab platform.
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Identification of a novel mutation in keratin 1 in a family with Epidermolytic Hyperkeratosis
Experimental Dermatology, 2000Co-Authors: Meral J. Arin, Mary A. Longley, Joseph A. Rothnagel, Ervin H. Epstein, Dennis R RoopAbstract:: Epidermolytic Hyperkeratosis (EHK) is a hereditary skin disorder typified by blistering due to cytolysis. One in 100,000 individuals is affected by this autosomal-dominant disease. The onset of the disease phenotype is typically at birth. Histological and ultrastructural examination of the epidermis shows a thickened stratum corneum and tonofilament clumping around the nucleus of suprabasal keratinocytes. Linkage studies localized the disease genes on chromosomes 12q and 17q which contain the type II and type I keratin gene clusters. Recently, several point mutations in the genes encoding the suprabasal keratins, K1 and K10, have been reported in EHK patients. We have investigated a large kindred affected by EHK and identified a new point mutation in the 2B region of keratin 1 (I107T), resulting from a T to C transition in codon 478.
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A novel substitution in keratin 10 in Epidermolytic Hyperkeratosis.
Journal of Investigative Dermatology, 1999Co-Authors: Meral J. Arin, Mary A. Longley, Joseph A. Rothnagel, Ingrun Anton-lamprecht, Gunter Kurze, Marcel Huber, Daniel Hohl, Dennis R RoopAbstract:Epidermolytic Hyperkeratosis is characterized by tonofilament clumping, cytolysis, and blister formation in suprabasal keratinocytes. It has been shown that the tonofilament aggregates in these areas are composed of keratin 1 (K1) and keratin 10 (K10), and several K1 and K10 point mutations have been identified as the molecular basis of Epidermolytic Hyperkeratosis. In this report we identify a novel, single base pair substitution resulting in an amino acid exchange from tyrosine to serine at residue 14 within the conserved 1A region of K10 (Y14S). This A to C transversion in codon 160 was only present in the affected individual and was associated with a very severe disease phenotype. Our observations are in agreement with previous reports documenting that this tyrosine residue, located at the beginning of the rod domain of type I keratins, is particularly sensitive to amino acid substitutions, and that alterations in this residue can have deleterious effects on filament assembly and stability.
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Prenatal diagnosis for keratin mutations to exclude transmission of Epidermolytic Hyperkeratosis
Prenatal Diagnosis, 1998Co-Authors: Joseph A. Rothnagel, Mary A. Longley, Michael T. Lin, Rhanda A. Holder, Paul G. Hazen, Moise L. Levy, Dennis R RoopAbstract:Epidermolytic Hyperkeratosis (bullous congenital ichthyosiform erythroderma) is an autosomal dominant skin disorder caused by mutations in keratins 1 and 10. We have used direct gene sequencing to ascertain the status of a 15 week fetus of parents whose first child was affected with this disorder. The parents show no clinical signs of Epidermolytic Hyperkeratosis but were concerned about the possibility of transmitting the disorder due to germline mosaicism. Molecular analysis of the affected son revealed a G to A mutation in codon 156 of keratin 10, resulting in an arginine to histidine substitution within the highly conserved 1A region. Codon 156 has been previously identified as a mutational hot spot and substitutions of this arginine residue are very common in Epidermolytic Hyperkeratosis patients. Analysis of genomic DNA isolated from amniotic cells showed that the fetus did not harbour this mutation and a healthy infant was eventually born that was unaffected by this disorder.
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Prenatal Diagnosis of Epidermolytic Hyperkeratosis by Direct Gene Sequencing
Journal of Investigative Dermatology, 1994Co-Authors: Joseph A. Rothnagel, Mary A. Longley, Rhanda A. Holder, Wolfgang Küster, Dennis R RoopAbstract:Epidermolytic Hyperkeratosis (bullous congenital ichthyosi-form erythroderma) is an autosomal dominant skin disorder caused by defects in the suprabasal keratins. Recently, mutations in the keratins 1 and 10 have been identified in patients with this disease. In this study, direct gene sequencing was used to establish the prenatal diagnosis in 15-week gestation twins at risk for Epidermolytic Hyperkeratosis. Direct sequence analysis of genomic DNA from the affected father and from both chorionic villus samples revealed a tyrosine to asparagine mutation at position 14 within the highly conserved 1A alpha-helical segment of keratin 10. None of the unaffected family members that were analyzed exhibit this mutation nor have polymorphic variations been observed in the normal population at this position. This residue is invariant in all type I keratins sequenced to date and is also conserved in related intermediate filament proteins such as vimentin and lamin. Given this high degree of conservation it is probable that any mutation at this position is deleterious and will result in disease.
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A mutational hot spot in keratin 10 (KRT 10) in patients with Epidermolytic Hyperkeratosis
Human Molecular Genetics, 1993Co-Authors: Joseph A. Rothnagel, Ingrun Anton-lamprecht, Marcel Huber, Daniel Hohl, Monte P. Fisher, Shelli M. Axtell, Mark R. Pittelkow, Dennis R RoopAbstract:Epidermolytic Hyperkeratosis (EHK), (bullous congenital ichthyosiform erythroderma), is an autosomal dominant human skin disorder. Recently, we and others have described mutations in keratins 1 and 10 (K1 and K10) in patients with this disease. Structure-function models predict that these mutations would impair normal filament assembly and function. We have extended our earlier studies to include 8 more incidences of EHK. In half of these families, we were unable to locate a mutation within the rod domains of either K1 or K10. However, polymorphic restriction site and sequence analysis of the other families revealed a mutational hot spot within the 1A alpha-helical segment of K10. These involve Arginine to Histidine, Arginine to Cysteine and Arginine to Leucine substitutions at residue 10 of the rod domain. Interestingly, mutations in the corresponding Arginine residue in keratin K14 have been identified in patients with epidermolysis bullosa simplex. The large number of mutations found at this position in both keratins K10 and K14 suggests that other epithelia cell disorders will be discovered that are caused by the corresponding mutation in related type I keratin genes.
Robert W. Dunstan - One of the best experts on this subject based on the ideXlab platform.
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mild recessive Epidermolytic Hyperkeratosis associated with a novel keratin 10 donor splice site mutation in a family of norfolk terrier dogs
British Journal of Dermatology, 2005Co-Authors: Kelly M. Credille, J.s. Minor, K.f. Barnhart, Robert W. DunstanAbstract:Summary Background Epidermolytic Hyperkeratosis in humans is caused by dominant-negative mutations in suprabasal epidermal keratins 1 and 10. However, spontaneous keratin mutations have not been confirmed in a species other than human. Objectives To describe an autosomal recessive, mild, nonpalmar/plantar Epidermolytic ichthyosis segregating in an extended pedigree of Norfolk terrier dogs due to a splice-site mutation in the gene encoding keratin 10 (KRT10). Methods Dogs were evaluated clinically, and skin samples were examined by light and electron microscopy. Genomic DNA samples and cDNA from skin RNA were sequenced and defined a mutation in KRT10. Consequences of the mutation were evaluated by assessing protein expression with immunohistochemistry and Western blotting and gene expression with real-time RT-PCR (reverse transcriptase-polymerase chain reaction). Results Adult dogs with the disease had generalized, pigmented Hyperkeratosis with epidermal fragility. Light microscopic examination defined epidermolysis with Hyperkeratosis; ultrastructural changes included a decrease in tonofilaments and abnormal filament aggregation in upper spinous and granular layer keratinocytes. Affected dogs were homozygous for a single base GTTT change in the consensus donor splice site of intron 5 in KRT10. Keratin 10 protein was not detected with immunoblotting in affected dogs. Heterozygous dogs were normal based on clinical and histological appearance and keratin 10 protein expression. The mutation caused activation of at least three cryptic or alternative splice sites. Use of the cryptic sites resulted in transcripts containing premature termination codons. One transcript could result in shortening of the proximal portion of the 2B domain before the stutter region. Quantitative real-time PCR indicated a significant decrease in KRT10 mRNA levels in affected dogs compared with wild-type dogs. Conclusions This disease is the first confirmed spontaneous keratin mutation in a nonhuman species and is the first reported recessive form of Epidermolytic Hyperkeratosis.