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Hiroshi Shimizu - One of the best experts on this subject based on the ideXlab platform.
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deficient stratum corneum intercellular lipid in a japanese patient with lamellar ichthyosis with a homozygous deletion mutation in sdr9c7
British Journal of Dermatology, 2017Co-Authors: Hiroshi Shimizu, Toshifumi Nomura, Takuya Takeichi, Hiroyuki Takama, Michihiro Kono, Kazumitsu Sugiura, Daisuke Watanabe, Michael A Simpson, John A. McgrathAbstract:Autosomal recessive Congenital ichthyosis (ARCI) is an umbrella term for inherited non-syndromic ichthyosis, which includes harlequin ichthyosis, lamellar ichthyosis (LI), Congenital Ichthyosiform Erythroderma and pleomorphic ichthyosis (also called self-healing/self-improving collodion baby).1 The clinical diversity is matched by genetic heterogeneity, with 11 genes currently implicated in the pathobiology of ARCI,2,3 including the most recent discovery of two missense mutations in SDR9C7 in three consanguineous Lebanese families.4 Here, we describe a case of ARCI (LI phenotype) that has a previously unreported homozygous deletion mutation in SDR9C7. We extend the spectrum of clinical features associated with SDR9C7 mutations, and identify deficient intercellular lipid and malformation of intercellular lipid layers in the stratum corneum. This article is protected by copyright. All rights reserved.
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*Co-corresponding authors:
2015Co-Authors: Keratin Gene, Masashi Akiyama, Daisuke Sawamura, Mutation Detected, Epidermal Nevus, Epidermolytic Hyperkeratosis, Satomi Ando, Masataka Abe, Hiroshi ShimizuAbstract:keratoderma Abbreviations: BCIE, bullous Congenital Ichthyosiform Erythroderma; EH, epidermolytic hyperkeratosis; K1, keratin 1; K10, keratin 10; LA-PCR, long and accurate PCR 1 Since 1994, four cases of epidermal nevus with epidermolytic hyperkeratosis (EH) caused by K10 gene mutations have been reported, although no K1 gene mutation has yet been reported. We detected a K1 gene (KRT1) mutation in epidermal nevus with EH in a 10-year-old Japanese male. The patient showed well-demarcated verrucous, hyperkeratotic plaques mainly on the trunk, covering 15 % of the entire body surface. No hyperkeratosis was seen on the palms or soles. He had no family history of skin disorders. His lesional skin showed typical granular degeneration and, ultrastructurally, clumped keratin filaments wer
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Partially disturbed lamellar granule secretion in mild Congenital Ichthyosiform Erythroderma with ALOX12B mutations.
The British journal of dermatology, 2010Co-Authors: Masashi Akiyama, Teruki Yanagi, N. Tabata, M. Yamada, Hiroshi ShimizuAbstract:Congenital Ichthyosiform Erythroderma (CIE) (OMIM 242100) is a major type of autosomal recessive Congenital ichthyosis (ARCI) showing generalized scaling and Erythroderma without blister formation. 1 Mutations in ALOX12B (OMIM 603741), encoding 12R-lipoxygenase (LOX), were identified in patients with CIE in 2002. 2 To date, several ALOX12B mutations have been reported in CIE families. 3,4 LOXs are a family of nonhaem, iron-containing dioxygenases which catalyse dioxygenation of fatty acids with one or more (Z,Z)-1,4-pentadiene moieties. 5 Three members of the human LOX family, 15-LOX-2, 12R-LOX and eLOX-3, are preferentially expressed in the skin. 5,6 The 12R-LOX pathway leads to hepoxilin B3 and trioxilin B3 7 resulting in 20-carboxy-trioxilin A3, 5 which is thought to be a key biological regulator in the skin. 8 12R-LOX deficiency results in a CIE phenotype in humans 2,9,10 and in mice 11,12 We report that a Japanese patient with CIE, harbouring one previously unreported ALOX12B mutation p.Arg442Gln and another known mutation p.Arg432X, showed partially disturbed secretion of lamellar granule (LG) contents in the epidermis.
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mild recessive bullous Congenital Ichthyosiform Erythroderma due to a previously unidentified homozygous keratin 10 nonsense mutation
Journal of Investigative Dermatology, 2008Co-Authors: Akiko Tsubota, Masashi Akiyama, Jean Kanitakis, Kaori Sakai, Toshifumi Nomura, A Claudy, Hiroshi ShimizuAbstract:We have identified a previously unreported homozygous nonsense mutation p.Cys427X in the keratin 10 (K10) gene (KRT10) in a Turkish girl with recessive bullous Congenital Ichthyosiform Erythroderma (BCIE) showing superficial blistering. p.Cys427X is located upstream of the previously reported homozygous truncation mutation within the same exon 6 causing mRNA decay. Immunohistochemical examination showed a complete absence of K10 protein in the patient's epidermis. The findings of this study suggest that K10 knockout patients show unique clinicopathological features of clinically mild BCIE with blisters occurring within the granular layer. In addition, the unaffected, heterozygous carriers of the mutation indicate that the K10 peptide from one normal allele alone is sufficient for keratin network formation.
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novel compound heterozygous nonsense and missense abca12 mutations lead to nonbullous Congenital Ichthyosiform Erythroderma
British Journal of Dermatology, 2008Co-Authors: Masashi Akiyama, Kaori Sakai, James R Mcmillan, Atsushi Hatamochi, S Yamazaki, Hiroshi ShimizuAbstract:Nonbullous Congenital Ichthyosiform Erythroderma (NBCIE) is a major type of autosomal recessive Congenital ichthyosis showing generalized severe scaling and Erythroderma without blister formation. In the classic NBCIE phenotype, the entire body is covered in fine, white scales over a background of erythrodermic skin.Mutations in ABCA12 are known to underlie harlequin ichthyosis (HI) and lamellar ichthyosis (LI). ABCA12 is a member of a large superfamily of ATP-binding cassette (ABC) transporters, which bind and hydrolyze ATP to transport various molecules across a limiting membrane or into a vesicle. The ABCA subfamily members are all thought to be lipid transporters.Lack of ABCA12 function subsequently leads to disruption of lamellar granule lipid transport in the upper keratinizing epidermal keratinocytes resulting in malformation of the stratum corneum intercellular lipid layers. Here we report that a compound heterozygote harbouring two novel ABCA12 mutations, c.3407G>A (p.Gly1136Asp) and c.5005C>T (p.Gln1669X), exhibited a typical NBCIE phenotype.© 2008 The Authors
John A. Mcgrath - One of the best experts on this subject based on the ideXlab platform.
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deficient stratum corneum intercellular lipid in a japanese patient with lamellar ichthyosis with a homozygous deletion mutation in sdr9c7
British Journal of Dermatology, 2017Co-Authors: Hiroshi Shimizu, Toshifumi Nomura, Takuya Takeichi, Hiroyuki Takama, Michihiro Kono, Kazumitsu Sugiura, Daisuke Watanabe, Michael A Simpson, John A. McgrathAbstract:Autosomal recessive Congenital ichthyosis (ARCI) is an umbrella term for inherited non-syndromic ichthyosis, which includes harlequin ichthyosis, lamellar ichthyosis (LI), Congenital Ichthyosiform Erythroderma and pleomorphic ichthyosis (also called self-healing/self-improving collodion baby).1 The clinical diversity is matched by genetic heterogeneity, with 11 genes currently implicated in the pathobiology of ARCI,2,3 including the most recent discovery of two missense mutations in SDR9C7 in three consanguineous Lebanese families.4 Here, we describe a case of ARCI (LI phenotype) that has a previously unreported homozygous deletion mutation in SDR9C7. We extend the spectrum of clinical features associated with SDR9C7 mutations, and identify deficient intercellular lipid and malformation of intercellular lipid layers in the stratum corneum. This article is protected by copyright. All rights reserved.
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new mutations in keratin 1 that cause bullous Congenital Ichthyosiform Erythroderma and keratin 2e that cause ichthyosis bullosa of siemens
British Journal of Dermatology, 2001Co-Authors: Neil V. Whittock, Robin A.j. Eady, W A D Griffiths, G H S Ashton, John A. McgrathAbstract:The intermediate filaments of epithelial cells are formed by keratins, a family of structurally related proteins, which are expressed in pairs of acidic (type I) and basic (type II) polypeptides in a tissue- and differentiation-specific manner. Mutations in the genes encoding several keratins have been implicated in the pathogenesis of diseases of keratinization. We report molecular analysis of two patients with the rare autosomal dominant disorders bullous Congenital Ichthyosiform Erythroderma (BCIE) and ichthyosis bullosa of Siemens (IBS). Previous studies have shown that these genodermatoses are due to mutations in the KRT1 and KRT2E genes, respectively. We report a new amino acid substitution mutation in codon 155 of KRT1 (valine to aspartic acid) in the conserved H1 domain of the protein in the patient with BCIE. We also report a novel amino acid substitution mutation in codon 192 of KRT2E (asparagine to lysine) in the conserved 1A helix initiation peptide of the protein in the patient with IBS. Our results demonstrate that these mutations are deleterious to keratin filament network stability and lead to specific clinical inherited disorders of keratinization.
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Genomic organization and amplification of the human epidermal type II keratin genes K1 and K5
Biochemical and biophysical research communications, 2000Co-Authors: Neil V. Whittock, Robin A.j. Eady, John A. McgrathAbstract:Abstract Keratins are a family of structurally related proteins that form the intermediate filament cytoskeleton in epithelial cells. Mutations in K1 and K5 result in the autosomal dominant disorders epidermolytic hyperkeratosis/bullous Congenital Ichthyosiform Erythroderma and epidermolysis bullosa simplex, respectively. Most disease-associated mutations are within exons encoding protein domains involved in keratin filament assembly. However, some mutations occur outside the mutation hot-spots and may perturb intermolecular interactions between keratins and other proteins, usually with milder clinical consequences. To screen the entire keratin 1 and keratin 5 genes we have characterized their intron–exon organization. The keratin 1 gene comprises 9 exons spanning approximately 5.6 kb on 12q, and the keratin 5 gene comprises 9 exons spanning approximately 6.1 kb on 12q. We have also developed a comprehensive PCR-based mutation detection strategy using primers placed on flanking introns followed by direct sequencing of the PCR products.
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Selective Involvement of Keratins K1 and K10 in the Cytoskeletal Abnormality of Epidermolytic Hyperkeratosis (Bullous Congenital Ichthyosiform Erythroderma)
Journal of Investigative Dermatology, 1992Co-Authors: Akemi Ishida-yamamoto, Mary R. Judge, Irene M. Leigh, John A. Mcgrath, E. Birgitte Lane, Robin A.j. EadyAbstract:Abstract Aggregation of tonofilaments within epidermal keratinocytes is a characteristic histologic feature of epidermolytic hyperkeratosis including the generalized form known as bullous Congenital Ichthyosiform Erythroderma. The histologic distribution and the keratin composition of the altered tonofilaments were investigated to determine whether the aggregation was specific to any particular keratin(s). Skin samples from seven patients and one mid-trimester fetus with generalized epidermolytic hyperkeratosis, and from one patient with a localized or "nevoid" form of epidermolytic hyperkeratosis, were analyzed by using various microscopical and immunocytochemical methods. A conjunctival sample and cultured epidermal keratinocytes from one patient with generalized epidermolytic hyperkeratosis were also examined by electron microscopy and immunocytochemistry. Ultrastructurally, tonofilament aggregates were distributed within the suprabasal stratified epithelial cell layers of the epidermis, of the infundibular part of outer root sheaths, and of the sebaceous ducts and sweat ducts, selectively following the known distribution pattern of keratins K1 and K10. The abnormal tonofilaments were not found in any other cutaneous epithelia, in conjunctival epithelium, or in cultured keratinocytes, where K1 and K10 are absent or only minimally expressed. Immunoelectron microscopy showed that among the keratins detected in suprabasal epidermolytic hyperkeratosis epidermis (K1/K5/K10/K14/K16), the aggregated tonofilaments predominantly expressed K1 and K10 rather than other keratins. These results suggest that the keratin filament abnormality in epidermolytic hyperkeratosis principally involves K1 and K10 and raise the question whether epidermolytic hyperkeratosis might be primarily a disorder of one or both of these keratins.
Masashi Akiyama - One of the best experts on this subject based on the ideXlab platform.
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*Co-corresponding authors:
2015Co-Authors: Keratin Gene, Masashi Akiyama, Daisuke Sawamura, Mutation Detected, Epidermal Nevus, Epidermolytic Hyperkeratosis, Satomi Ando, Masataka Abe, Hiroshi ShimizuAbstract:keratoderma Abbreviations: BCIE, bullous Congenital Ichthyosiform Erythroderma; EH, epidermolytic hyperkeratosis; K1, keratin 1; K10, keratin 10; LA-PCR, long and accurate PCR 1 Since 1994, four cases of epidermal nevus with epidermolytic hyperkeratosis (EH) caused by K10 gene mutations have been reported, although no K1 gene mutation has yet been reported. We detected a K1 gene (KRT1) mutation in epidermal nevus with EH in a 10-year-old Japanese male. The patient showed well-demarcated verrucous, hyperkeratotic plaques mainly on the trunk, covering 15 % of the entire body surface. No hyperkeratosis was seen on the palms or soles. He had no family history of skin disorders. His lesional skin showed typical granular degeneration and, ultrastructurally, clumped keratin filaments wer
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Partially disturbed lamellar granule secretion in mild Congenital Ichthyosiform Erythroderma with ALOX12B mutations.
The British journal of dermatology, 2010Co-Authors: Masashi Akiyama, Teruki Yanagi, N. Tabata, M. Yamada, Hiroshi ShimizuAbstract:Congenital Ichthyosiform Erythroderma (CIE) (OMIM 242100) is a major type of autosomal recessive Congenital ichthyosis (ARCI) showing generalized scaling and Erythroderma without blister formation. 1 Mutations in ALOX12B (OMIM 603741), encoding 12R-lipoxygenase (LOX), were identified in patients with CIE in 2002. 2 To date, several ALOX12B mutations have been reported in CIE families. 3,4 LOXs are a family of nonhaem, iron-containing dioxygenases which catalyse dioxygenation of fatty acids with one or more (Z,Z)-1,4-pentadiene moieties. 5 Three members of the human LOX family, 15-LOX-2, 12R-LOX and eLOX-3, are preferentially expressed in the skin. 5,6 The 12R-LOX pathway leads to hepoxilin B3 and trioxilin B3 7 resulting in 20-carboxy-trioxilin A3, 5 which is thought to be a key biological regulator in the skin. 8 12R-LOX deficiency results in a CIE phenotype in humans 2,9,10 and in mice 11,12 We report that a Japanese patient with CIE, harbouring one previously unreported ALOX12B mutation p.Arg442Gln and another known mutation p.Arg432X, showed partially disturbed secretion of lamellar granule (LG) contents in the epidermis.
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mild recessive bullous Congenital Ichthyosiform Erythroderma due to a previously unidentified homozygous keratin 10 nonsense mutation
Journal of Investigative Dermatology, 2008Co-Authors: Akiko Tsubota, Masashi Akiyama, Jean Kanitakis, Kaori Sakai, Toshifumi Nomura, A Claudy, Hiroshi ShimizuAbstract:We have identified a previously unreported homozygous nonsense mutation p.Cys427X in the keratin 10 (K10) gene (KRT10) in a Turkish girl with recessive bullous Congenital Ichthyosiform Erythroderma (BCIE) showing superficial blistering. p.Cys427X is located upstream of the previously reported homozygous truncation mutation within the same exon 6 causing mRNA decay. Immunohistochemical examination showed a complete absence of K10 protein in the patient's epidermis. The findings of this study suggest that K10 knockout patients show unique clinicopathological features of clinically mild BCIE with blisters occurring within the granular layer. In addition, the unaffected, heterozygous carriers of the mutation indicate that the K10 peptide from one normal allele alone is sufficient for keratin network formation.
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novel compound heterozygous nonsense and missense abca12 mutations lead to nonbullous Congenital Ichthyosiform Erythroderma
British Journal of Dermatology, 2008Co-Authors: Masashi Akiyama, Kaori Sakai, James R Mcmillan, Atsushi Hatamochi, S Yamazaki, Hiroshi ShimizuAbstract:Nonbullous Congenital Ichthyosiform Erythroderma (NBCIE) is a major type of autosomal recessive Congenital ichthyosis showing generalized severe scaling and Erythroderma without blister formation. In the classic NBCIE phenotype, the entire body is covered in fine, white scales over a background of erythrodermic skin.Mutations in ABCA12 are known to underlie harlequin ichthyosis (HI) and lamellar ichthyosis (LI). ABCA12 is a member of a large superfamily of ATP-binding cassette (ABC) transporters, which bind and hydrolyze ATP to transport various molecules across a limiting membrane or into a vesicle. The ABCA subfamily members are all thought to be lipid transporters.Lack of ABCA12 function subsequently leads to disruption of lamellar granule lipid transport in the upper keratinizing epidermal keratinocytes resulting in malformation of the stratum corneum intercellular lipid layers. Here we report that a compound heterozygote harbouring two novel ABCA12 mutations, c.3407G>A (p.Gly1136Asp) and c.5005C>T (p.Gln1669X), exhibited a typical NBCIE phenotype.© 2008 The Authors
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Congenital Ichthyosiform Erythroderma mimicking ichthyosis bullosa of siemens
British Journal of Dermatology, 2007Co-Authors: Akiko Tsubota, Masashi Akiyama, Kaori Sakai, Teruki Yanagi, James R Mcmillan, A Higashi, Hiroshi ShimizuAbstract:Bullous Congenital Ichthyosiform Erythroderma (BCIE) is a severe autosomal dominant inherited skin disorder caused by keratin 1 (K1) gene (KRT1) or keratin 10 (K10) gene (KRT10) mutations. Patients with BCIE show generalized erythema and bullae from birth. Histopathologically, granular degeneration is seen in the middle to upper epidermis. Keratin clumps predominantly comprising K1 and K10 are observed in the spinous and granular layers.Ichthyosis bullosa of Siemens (IBS) is a relatively mild ichthyosis with superficial blister formation caused by keratin 2e (K2e) gene (KRT2E) mutations and in which granular degeneration is restricted to the uppermost spinous and granular layers. Patients with IBS who had severe skin phenotypes and who had previously been misdiagnosed with BCIE from their clinicopathological findings were correctly diagnosed by molecular genetic testing methods. Conversely, here we report a family with mild BCIE showing clinical and histological features similar to IBS. A heterozygous missense mutation p.Glu478Asp in KRT1 was detected in this family.We previously reported that the differential diagnosis of IBS and BCIE is difficult in some instances and molecular genetic testing is useful to differentiate IBS from BCIE. In the present report, we show that p.Glu478Asp in K1 leads to clinicopathological features mimicking IBS, i.e. superficial blisters and granular degeneration restricted to the uppermost spinous and granular layers of the epidermis. These results further confirm that there are many cases of BCIE and IBS in which the correct differential diagnosis is problematic unless mutational analysis is performed.© 2007 British Association of Dermatologists
Dennis R Roop - One of the best experts on this subject based on the ideXlab platform.
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A Novel Helix Termination Mutation in Keratin 10 in Annular Epidermolytic Ichthyosis, a Variant of Bullous Congenital Ichthyosiform Erythroderma
The Journal of investigative dermatology, 1998Co-Authors: Yasushi Suga, Karynne O. Duncan, Peter Heald, Dennis R RoopAbstract:Annular epidermolytic ichthyosis is a distinct phenotypic variant of bullous Congenital Ichthyosiform Erythroderma that has recently been described in two separate kindreds. Individuals with this variant present with bullous ichthyosis in early childhood and hyperkeratotic lichenified plaques in the flexural areas and extensor surfaces at later ages. Characteristically, they also develop intermittent bouts of annular and polycyclic, erythematous, scaly plaques on the trunk and proximal extremities. We now describe a third kindred with annular epidermolytic ichthyosis. Molecular analysis of this family revealed a novel mutation resulting in an isoleucine to threonine substitution at residue 107 (codon 446) within the highly conserved helix termination motif at the end of the rod domain of keratin 10.
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a novel dinucleotide mutation in keratin 10 in the annular epidermolytic ichthyosis variant of bullous Congenital Ichthyosiform Erythroderma
Journal of Investigative Dermatology, 1997Co-Authors: Marcel Huber, Daniel Hohl, Mary A. Longley, Joseph A. Rothnagel, Gwangyeol Joh, Heiko Traupe, Dieter Metze, Dorothee Nashan, Dennis R RoopAbstract:Annular epidermolytic ichthyosis has recently been delineated as a distinct clinical phenotype within the spectrum of epidermolytic keratinization disorders. The pattern of inheritance of the disorder is consistent with an autosomal dominant mode of transmission. Here we report a second incidence of this disorder in a family with two affected generations. The proband suffered from bullous ichthyosis and had bouts of disease activity associated with the development of numerous annular and polycyclic erythematous, hyperkeratotlc plaques on the trunk and the proximal extremities. Histologic examination showed the typical pathology of epidermolytic hyperkeratosis, and ultrastructural analysis revealed abnormal keratin filament networks and tonofilament clumping with a perinuclear distribution. Molecular analysis revealed a novel tandem CG to GA 2-bp mutation in the same allele of keratin 10 in affected individuals, resulting in an arginine to glutamate substitution at residue 83 (R83E) of the 2B helical segment. We conclude that annular epidermolytic ichthyosis should be considered a variant of bullous Congenital Ichthyosiform Erythroderma.
Robin A.j. Eady - One of the best experts on this subject based on the ideXlab platform.
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new mutations in keratin 1 that cause bullous Congenital Ichthyosiform Erythroderma and keratin 2e that cause ichthyosis bullosa of siemens
British Journal of Dermatology, 2001Co-Authors: Neil V. Whittock, Robin A.j. Eady, W A D Griffiths, G H S Ashton, John A. McgrathAbstract:The intermediate filaments of epithelial cells are formed by keratins, a family of structurally related proteins, which are expressed in pairs of acidic (type I) and basic (type II) polypeptides in a tissue- and differentiation-specific manner. Mutations in the genes encoding several keratins have been implicated in the pathogenesis of diseases of keratinization. We report molecular analysis of two patients with the rare autosomal dominant disorders bullous Congenital Ichthyosiform Erythroderma (BCIE) and ichthyosis bullosa of Siemens (IBS). Previous studies have shown that these genodermatoses are due to mutations in the KRT1 and KRT2E genes, respectively. We report a new amino acid substitution mutation in codon 155 of KRT1 (valine to aspartic acid) in the conserved H1 domain of the protein in the patient with BCIE. We also report a novel amino acid substitution mutation in codon 192 of KRT2E (asparagine to lysine) in the conserved 1A helix initiation peptide of the protein in the patient with IBS. Our results demonstrate that these mutations are deleterious to keratin filament network stability and lead to specific clinical inherited disorders of keratinization.
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novel splice site mutation in keratin 1 underlies mild epidermolytic palmoplantar keratoderma in three kindreds
Journal of Investigative Dermatology, 2001Co-Authors: Sarah J Hatsell, Robin A.j. Eady, Patricia J C Doppinghepenstal, I M Leigh, Lena Wennerstrand, Colin S Munro, David P KelsellAbstract:We report a novel mutation in the exon 6 splice donor site of keratin 1 (G4134A) that segregates with a palmoplantar keratoderma in three kindreds. The nucleotide substitution leads to the utilization of a novel in-frame splice site 54 bases downstream of the mutation with the subsequent insertion of 18 amino acids into the 2B rod domain. This mutation appears to have a milder effect than previously described mutations in the helix initiation and termination sequence on the function of the rod domain, with regard to filament assembly and stability. Affected individuals displayed only mild focal epidermolysis in the spinous layer of palmoplantar epidermis, in comparison with cases of bullous Congenital Ichthyosiform Erythroderma also due to keratin 1 mutations, which show widespread and severe epidermolysis. This study describes a novel mutation in KRT1 that results in a phenotype distinct from classical bullous Congenital Ichthyosiform Erythroderma.
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Genomic organization and amplification of the human epidermal type II keratin genes K1 and K5
Biochemical and biophysical research communications, 2000Co-Authors: Neil V. Whittock, Robin A.j. Eady, John A. McgrathAbstract:Abstract Keratins are a family of structurally related proteins that form the intermediate filament cytoskeleton in epithelial cells. Mutations in K1 and K5 result in the autosomal dominant disorders epidermolytic hyperkeratosis/bullous Congenital Ichthyosiform Erythroderma and epidermolysis bullosa simplex, respectively. Most disease-associated mutations are within exons encoding protein domains involved in keratin filament assembly. However, some mutations occur outside the mutation hot-spots and may perturb intermolecular interactions between keratins and other proteins, usually with milder clinical consequences. To screen the entire keratin 1 and keratin 5 genes we have characterized their intron–exon organization. The keratin 1 gene comprises 9 exons spanning approximately 5.6 kb on 12q, and the keratin 5 gene comprises 9 exons spanning approximately 6.1 kb on 12q. We have also developed a comprehensive PCR-based mutation detection strategy using primers placed on flanking introns followed by direct sequencing of the PCR products.
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gene targeting at the mouse cytokeratin 10 locus severe skin fragility and changes of cytokeratin expression in the epidermis
Journal of Cell Biology, 1996Co-Authors: R M Porter, David W. Melton, Sabine Leitgeb, O. Swensson, Robin A.j. Eady, Thomas M MaginAbstract:Bullous Congenital Ichthyosiform Erythroderma (BCIE) is a dominantly inherited blistering skin disorder caused by point mutations in the suprabasal cytokeratins 1 or 10. Targeting the murine cytokeratin 10 gene in ES cells resulted in mice with different phenotypes in the homozygotes and heterozygotes; both of which exhibit similarities to specific clinical characteristics of BCIE. Homozygotes suffered from severe skin fragility and died shortly after birth. Heterozygotes were apparently unaffected at birth, but developed hyperkeratosis with age. In both genotypes, aggregation of cytokeratin intermediate filaments, changes in cytokeratin expression, and alterations in the program of epidermal differentiation were observed. In addition we demonstrate, for the first time, the existence of the murine equivalent of human cytokeratin 16.
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Selective Involvement of Keratins K1 and K10 in the Cytoskeletal Abnormality of Epidermolytic Hyperkeratosis (Bullous Congenital Ichthyosiform Erythroderma)
Journal of Investigative Dermatology, 1992Co-Authors: Akemi Ishida-yamamoto, Mary R. Judge, Irene M. Leigh, John A. Mcgrath, E. Birgitte Lane, Robin A.j. EadyAbstract:Abstract Aggregation of tonofilaments within epidermal keratinocytes is a characteristic histologic feature of epidermolytic hyperkeratosis including the generalized form known as bullous Congenital Ichthyosiform Erythroderma. The histologic distribution and the keratin composition of the altered tonofilaments were investigated to determine whether the aggregation was specific to any particular keratin(s). Skin samples from seven patients and one mid-trimester fetus with generalized epidermolytic hyperkeratosis, and from one patient with a localized or "nevoid" form of epidermolytic hyperkeratosis, were analyzed by using various microscopical and immunocytochemical methods. A conjunctival sample and cultured epidermal keratinocytes from one patient with generalized epidermolytic hyperkeratosis were also examined by electron microscopy and immunocytochemistry. Ultrastructurally, tonofilament aggregates were distributed within the suprabasal stratified epithelial cell layers of the epidermis, of the infundibular part of outer root sheaths, and of the sebaceous ducts and sweat ducts, selectively following the known distribution pattern of keratins K1 and K10. The abnormal tonofilaments were not found in any other cutaneous epithelia, in conjunctival epithelium, or in cultured keratinocytes, where K1 and K10 are absent or only minimally expressed. Immunoelectron microscopy showed that among the keratins detected in suprabasal epidermolytic hyperkeratosis epidermis (K1/K5/K10/K14/K16), the aggregated tonofilaments predominantly expressed K1 and K10 rather than other keratins. These results suggest that the keratin filament abnormality in epidermolytic hyperkeratosis principally involves K1 and K10 and raise the question whether epidermolytic hyperkeratosis might be primarily a disorder of one or both of these keratins.