A glutamate to lysine mutation at the end of 2B rod domain of keratin 2e gene in ichthyosis bullosa of … (1999 Feb)
A glutamate to lysine mutation at the end of 2B rod domain of keratin 2e gene in ichthyosis bullosa of siemens . ichthyosis bullosa of siemens is a rare autosomal dominant skin disorder whose clinical findings are quite similar to those of epidermolytic hyperkeratosis . The differences between those two diseases include absence of erythroderma and different distributions in the skin in ichthyosis bullosa of siemens . recent studies have confirmed that ichthyosis bullosa of siemens is caused by the mutation in the keratin 2e ( K2e ) gene , which is expressed in the upper spinous and granular layers . We have identified a sporadic case of ichthyosis bullosa of siemens ; based on diagnosis by histopathological findings , the K2e gene of the patient was analysed . direct sequencing of PCR products revealed a single base change in sequences encoding the highly conserved end of the 2B rod domain segment of the K2e gene . This mutation results in substitution of the codon for glutamic acid by a codon for lysine in position 493 in K2e ( e493k ) . mutations of the K2e gene involving five different residue positions ( q187p , t485p , l490p , e493d , e493k and e494k ) are known to cause ichthyosis bullosa of siemens . Of these sites , E493 , which is conserved in type I and type II keratin genes , is the most frequently altered amino acid in the K2e gene . these data together suggest that this …

Ichthyosis bullosa of siemens a disease involving keratin 2e. (1994 Oct)
ichthyosis bullosa of siemens a disease involving keratin 2e . ichthyosis bullosa of siemens ( IBS ) is a congenital bullous ichthyosis without erythroderma . In contrast to bullous congenital ichthyosiform erythroderma ( BCIE ) , there is a relatively mild involvement of the skin and epidermolytic hyperkeratosis ( EHK ) is restricted to the upper suprabasal layers of the epidermis . tonofilament aggregation was observed by EM in suprabasal cells from affected patients in the two families under study , indicative of a keratin abnormality . keratin 2e is a differentiation specific type II keratin expressed suprabasally in the epidermis . Part of the K2e gene was amplified by polymerase chain reaction using genomic DNA from affected and unaffected individuals from two IBS families . direct sequencing of polymerase chain reaction products revealed a point mutation in the highly conserved helix termination motif , producing the protein sequence change llegee llegke . This mutation was found in all affected members of a five generation kindred and also in a sporadic case in a second unrelated family . No mutation was seen in unaffected individuals . The mutation destroys a MnlI restriction site , which allowed exclusion of the mutation from a population of 50 unaffected unrelated individuals by restriction fragment analysis of K2e PCR products . This is the sixth keratin gene found to be involved in an inherited epidermal disorder .

Human keratin diseases : hereditary fragility of specific epithelial tissues. (1997 Jun)
human keratin diseases : hereditary fragility of specific epithelial tissues . keratins are heteropolymeric proteins which form the intermediate filament cytoskeleton in epithelial cells . since 1991 , mutations in several keratin genes have been found to cause a variety of human diseases affecting the epidermis and other epithelial structures . epidermolysis bullosa simplex ( EBS ) was the first mechanobullous disease for which the underlying genetic lesion was found , with mutations in both the K5 and K14 genes rendering basal epidermal keratinocytes less resilient to trauma , resulting in skin fragility . The site of mutation in the keratin protein correlates with phenotypic severity in this disorder . since mutations were identified in the basal cell keratins , the total number of keratin genes associated with diseases has risen to eleven . The rod domains of suprabasal keratins K1 and K10 are mutated in bullous congenital ichthyosiform erythroderma ( BCIE ; also called epidermolytic hyperkeratosis , EH ) and mosaicism for K1 / K10 mutations results in a nevoid distribution of EH . An unusual mutation in the VI domain of K1 has also been found to cause diffuse non epidermolytic palmoplantar keratoderma ( dneppk ) . mutations in palmoplantar specific keratin K9 cause epidermolytic palmoplantar keratoderma ( EPPK ) and mutations in the late differentiation suprabasal keratin K2e cause ichthyosis bullosa of siemens ( IBS ) . In the last year or so , mutations were discovered in differentiation specific keratins K6a and K16 causing pachyonychia congenita …

Ichthyosis bullosa of siemens : its correct diagnosis facilitated by molecular genetic testing. (2005 Jun)
ichthyosis bullosa of siemens : its correct diagnosis facilitated by molecular genetic testing . ichthyosis bullosa of siemens ( IBS , MIM 146800 ) is a unique congenital ichthyosis characterized by mild epidermal hyperkeratosis over flexural areas , blister formation and the development of superficially denuded areas of hyperkeratotic skin . It is clinically difficult to distinguish severe IBS from mild bullous congenital ichthyosiform erythroderma ( BCIE , MIM 113800 ) . In the current literature , 19 IBS families with keratin 2e ( K2e ) mutations have been reported , despite only five IBS families having been reported before the first identification of K2e mutation in 1994 . We studied four patients from three japanese IBS families . They had previously been misdiagnosed as having BCIE before the correct diagnosis was made after mutation detection . To detect the pathogenic mutations , we performed direct sequencing of the entire coding regions of krt2e encoding K2e in the patients and healthy family members . K2e mutations , a 1469t C transition ( l490p ) and a 1477g A transition ( e493k ) within the conserved 2B helix termination motif of the rod domain were detected in the families and the definite diagnosis of IBS was made in the four cases . The present results indicate that IBS is not such a rare entity as was previously thought , and accurate diagnosis is now available by mutation analysis .

Genetic linkage of the keratin type II gene cluster with ichthyosis bullosa of siemens and with autosomal dominant ichthyosis exfoliativa. (1994 Oct)
genetic linkage of the keratin type II gene cluster with ichthyosis bullosa of siemens and with autosomal dominant ichthyosis exfoliativa . ichthyosis bullosa of siemens is an autosomal dominant disease characterized by mild hyperkeratosis and blistering . autosomal dominant ichthyosis exfoliativa is a recently described disease with clinical features similar to ichthyosis bullosa of siemens , but in contrast to ichthyosis bullosa of siemens no histologic signs typical for epidermolytic hyperkeratosis are observed . We used linkage analysis to test whether keratin gene mutations might underlie both diseases . This analysis showed linkage of both disorders with the region of chromosome 12 in which the keratin type II gene cluster is located . The keratin type I gene cluster on chromosome 17 is excluded . these data , combined with clinical observations , strongly suggest that the genes coding for keratin 1 or keratin 2e , both expressed in the suprabasal compartment of the epidermis and located in the type II gene cluster , are candidate genes for ichthyosis bullosa of siemens and ichthyosis exfoliativa .

Ichthyosis bullosa of siemens is caused by mutations in the keratin 2e gene. (1994 Oct)
ichthyosis bullosa of siemens is caused by mutations in the keratin 2e gene . ichthyosis bullosa of siemens is a blistering disorder with autosomal dominant inheritance . The disease resembles bullous congenital ichthyosiform erythroderma but is less severe . keratins K1 and K10 have been implicated in bullous congenital ichthyosiform erythroderma . linkage analysis pointed to the involvement of a keratin type II gene ( 12q11 13 ) in ichthyosis bullosa of siemens . mutations in the highly conserved regions of K1 , a member of the type II gene cluster , were excluded . The gene coding for keratin 2e is also located in the type II gene cluster and the expression of the gene coincides with the occurrence of epidermolytic hyperkeratosis . sequence analysis revealed the presence of mutations in the K2e gene in patients with ichthyosis bullosa of siemens . three different mutations were detected , one in the 1A domain and two in the 2B domain of the rod . furthermore , histologic and ultrastructural examination of skin biopsies indicated that ichthyosis exfoliativa is identical to ichthyosis bullosa of siemens . This was confirmed by the results of the molecular analysis . In the family diagnosed as ichthyosis exfoliativa , a mutation was detected that was identical to the mutation found in one of the families with ichthyosis bullosa of siemens .

The keratins and their disorders. (2004 Oct)
The keratins and their disorders . diseases caused by mutations in gene encoding keratin intermediate filaments ( IF ) are characterized by a loss of structural integrity in the cells expressing those keratins in vivo . This is manifested as cell fragility , compensatory epidermal hyperkeratosis , and keratin filament aggregation in some affected tissues . keratin disorders are a novel molecular category including quite different phenotypes such as epidermolysis bullosa simplex ( EBS ) , bullous congenital ichthyosiform erthroderma ( BCIE ) , pachyonychia congenital ( PC ) , steatocystoma multiplex , ichthyosis bullosa of siemens ( IBS ) , and white sponge nevus ( WSN ) of the orogenital mucosa .

A novel mutation in the 1A domain of keratin 2e in ichthyosis bullosa of siemens. (1999 Apr)
A novel mutation in the 1A domain of keratin 2e in ichthyosis bullosa of siemens . ichthyosis bullosa of siemens ( IBS ) is a rare autosomal dominant skin disorder with clinical features similar to epidermolytic hyperkeratosis ( EHK ) . Both diseases have been linked to the type II keratin cluster on chromosome 12q . hyperkeratosis and blister formation are relatively mild in IBS compared with EHK , and the lysis of keratinocytes is restricted to the upper spinous and granular layers of the epidermis of IBS patients , whereas in EHK lysis occurs in the lower spinous layer . recently , mutations in the helix initiation and termination motifs of keratin 2e ( K2e ) have been described in IBS patients . The majority of the mutations reported to date lie in the 2B region . In this report , we have examined a large kindred in which the disease was originally diagnosed as EHK and mapped to the type II keratin cluster on chromosome 12q . molecular analysis revealed a novel amino acid substitution at the beginning of the conserved 1A region of the rod domain ( I4N ) of K2e , resulting from a T to A transversion in codon 188 .

Genomic organization and fine mapping of the keratin 2e gene ( krt2e ) : K2e V1 domain polymorphism and novel … (1998 Nov)
genomic organization and fine mapping of the keratin 2e gene ( krt2e ) : K2e V1 domain polymorphism and novel mutations in ichthyosis bullosa of siemens . We and others have previously shown that ichthyosis bullosa of siemens , an autosomal dominant disorder characterized by epidermal thickening and blistering , is caused by mutations in the late differentiation keratin K2e . Here , we have determined the genomic organization and complete sequence of the krt2e gene , which consists of nine exons , spanning 7634 bp of DNA . The gene was mapped by high resolution radiation hybrid mapping to the interval between microsatellite markers d12s368 and CHLC . gata11b02 . 1112 . several intragenic polymorphisms were detected , including an 18 bp duplication in exon 1 , corresponding to the V1 domain of the K2e polypeptide . genomic polymerase chain reaction conditions were optimized for all exons , and two novel mutations , n192y in the 1A domain and e482k in the 2B domain of K2e , were found in ichthyosis bullosa of siemens families . mutations were excluded from 50 normal unrelated individuals by restriction analysis . these results emphasize that mutations in K2e underlie ichthyosis bullosa of siemens and provide a comprehensive mutation detection strategy for ongoing studies of keratinizing disorders .

New mutations in keratin 1 that cause bullous congenital ichthyosiform erythroderma and keratin 2e that cause ichthyosis bullosa of siemens. (2001 Sep)
New mutations in keratin 1 that cause bullous congenital ichthyosiform erythroderma and keratin 2e that cause ichthyosis bullosa of siemens . 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 .

Mutations in the rod domain of keratin 2e in patients with ichthyosis bullosa of siemens. (1994 Dec)
mutations in the rod domain of keratin 2e in patients with ichthyosis bullosa of siemens . ichthyosis bullosa of siemens ( IBS ) is an autosomal dominant skin disorder that resembles epidermolytic hyperkeratosis ( EHK ) . We have identified mutations in two families originally diagnosed with EHK and in four families diagnosed with IBS at the same codon in the highly conserved carboxy terminal of the rod domain of keratin 2e , thus revealing a mutational hot spot . Our results allow a differential diagnosis to be made between IBS and EHK at the genetic level and we suggest that patients diagnosed with EHK , but lacking keratin K1 or K10 mutations , should be re examined for mutations in their K2e genes .

A novel threonine proline mutation at the end of 2B rod domain in the keratin 2e chain in ichthyosis bullosa … (1997 Jul)
A novel threonine proline mutation at the end of 2B rod domain in the keratin 2e chain in ichthyosis bullosa of siemens . We report a novel mutation in a case of ichthyosis bullosa of siemens that results in a threonine proline substitution in a novel location , codon 485 in a highly conserved residue position of the iatyrkllege consensus motif at the end of the 2B rod domain segment of the keratin 2e chain . The disease phenotype is consistent with the inappropriate substitution of a proline near the end of the rod domain , because it lies near the predicted molecular overlap region of coiled coil molecules , which is critical for the maintenance of the structural integrity of keratin intermediate filaments .

Primers for exon specific amplification of the KRT5 gene : identification of novel and recurrent mutations in epidermolysis bullosa simplex … (1997 Mar)
primers for exon specific amplification of the KRT5 gene : identification of novel and recurrent mutations in epidermolysis bullosa simplex patients . The KRT5 and krt14 genes encode the proteins keratin 5 and 14 , respectively , which are the primary structural components of the 10 nm intermediate filaments of the mitotic epidermal basal cells . A single mutation in either gene can disrupt the keratin intermediate filament cytoskeleton , resulting in the skin fragility and blistering that is characteristic of the group of inherited disorders known as epidermolysis bullosa simplex . We have established a mutation detection system that facilitates KRT5 gene analysis from leukocyte genomic DNA , obviating the need for a skin sample or keratinocyte culture for cDNA synthesis . KRT5 intronic regions that flanked each exon were sequenced and sets of facing intronic primers were designed for specific amplification of each of the nine KRT5 exons . direct sequencing of KRT5 amplified exons identified three novel missense mutations . One mutation recurred in two unrelated patients with sporadic EBS . This glutamate to lysine substitution ( e477k ) , located in the highly conserved kllege motif at the end of the central rod domain , is the third recurrent mutation identified in dominant epidermolysis bullosa simplex disease . The corresponding glutamate in keratin 2e was previously reported to be frequently mutated in ichthyosis bullosa of siemens , suggesting that this highly conserved residue may be a potential mutational hot spot in other type II keratins or …

Arginine in the beginning of the 1A rod domain of the keratin 10 gene is the hot spot for the … (1999 May)
arginine in the beginning of the 1A rod domain of the keratin 10 gene is the hot spot for the mutation in epidermolytic hyperkeratosis . keratin intermediate filaments are expressed in specific type I / type II pairs in the stage of differentiation of keratinocytes . The mutations in the keratin genes expressed in the epidermis are etiologically responsible for several epidermal genetic skin diseases , such as epidermolysis bullosa simplex , epidermolytic hyperkeratosis ( EHK ) , ichthyosis bullosa of siemens , palmoplantar keratoderma , pachyonchia congenita and white sponge nevus . The mutations of keratins 1 / 10 which are expressed in spinous and granular layers are confirmed to cause EHK . there are several trials to correlate between the clinical phenotypes and sites of mutations of the keratin genes . One of these is that EHK is divided into two groups : the palms and soles involvement ( PS ) group and the non palms and soles ( NPS ) group . So far the PS group had the mutations in the keratin 1 and the NPS group in keratin 10 . Most of the mutations of the NPS group were reported in the beginning of the 1A rod domain and over 2 / 3 of the mutations in the 1A rod domain were the base pair substitution of arginine . Here we find two different mutations in two unrelated korean kindreds classified as NPS group r156c and r156h in the 1A rod domain of keratin 10 …

Ichthyosis bullosa of siemens : report of a family with evidence of a keratin 2e mutation , and a review … (2000 Mar)
ichthyosis bullosa of siemens : report of a family with evidence of a keratin 2e mutation , and a review of the literature . We report a large family with ichthyosis bullosa of siemens ( IBS ) including eight affected members spanning three generations . The classical features of the disease were consistently observed with blistering , superficial peeling of the skin , and localized lichenified hyperkeratosis mainly confined to the limbs . phenotypic variation , however , was also observed with some individuals exhibiting unusual clinical features . specifically , the index patient was erythrodermic at birth ; she subsequently developed a widespread pustular eruption . erythroderma is classically absent in IBS and pustulation is very unusual . She also had hypertrichosis of the limbs , as did an affected female first cousin . This has not previously been reported in IBS . electron microscopy showed complex aggregates of keratin in the spinous and granular layers associated , in places , with remarkably little cell lysis . sequencing of genomic DNA revealed a mutation ( e493k ) in keratin 2e . A review of the literature on IBS indicates that e493k is the most commonly reported mutation to date and might represent a mutational hotspot for this disease .

A novel asparagine aspartic acid mutation in the rod 1A domain in keratin 2e in a japanese family with ichthyosis … (2000 Mar)
A novel asparagine aspartic acid mutation in the rod 1A domain in keratin 2e in a japanese family with ichthyosis bullosa of siemens . ichthyosis bullosa of siemens is a unique type of congenital ichthyosis characterized by mild hyperkeratosis over the flexural areas and blister formation after mechanical trauma and superficial denuded areas in the hyperkeratotic skin . recently , mutations in the helix initiation or termination motifs of keratin 2e ( krt2e ) have been described in ichthyosis bullosa of siemens patients . The majority of the mutations reported to date lie in the 2B region . We report a novel amino acid substitution mutation ( asparagine aspartic acid ) in codon 192 at the conserved 1A helix initiation site of the rod domain of krt2e in a japanese family with ichthyosis bullosa of siemens . Our data indicate aspartic acid substitution in codon 192 in the 1A helix initiation site is deleterious to keratin filament network integrity and leads to ichthyosis bullosa of siemens phenotype .

A novel mutation in the 2B domain of keratin 2e causing ichthyosis bullosa of siemens. (2001 Feb)
A novel mutation in the 2B domain of keratin 2e causing ichthyosis bullosa of siemens . ichthyosis bullosa of siemens ( IBS ; MIM : 146800 ) is an autosomal dominant disorder of keratinization characterized by epidermolytic hyperkeratosis without erythroderma . The clinical features are less marked than those of bullous congenital ichthyosiform erythroderma with relatively mild hyperkeratosis usually limited to the skin flexures . mutations in the epithelial cytokeratin 2e ( K2e ) , which is expressed in a differentiation specific fashion in the upper spinous and granular layers of the epidermis , have been shown to cause IBS . We detected a novel mutation in a three generation kindred with IBS ( 1448t A ) within exon 7 of the krt2e gene . This is predictive of an i483n substitution in the 2B domain of K2e . This extends the range of mutations reported to date and illustrates the usefulness of molecular genetics in the diagnosis of this disorder .

The molecular basis for inherited bullous diseases. (1996 Dec)
The molecular basis for inherited bullous diseases . In the past 5 years enormous progress have been made in our understanding of the molecular basis for a number of inherited skin diseases characterized by easy blistering of the skin and the mucous membranes after minor physical trauma . This increased fragility of the skin or its appendages is due to molecular defects in genes coding for different intra and extracellular structural proteins which are responsible for mechanical strength at their sites of expression . these diseases encompass the group of epidermolysis bullosa and disorders of cornification such as bullous forms of ichthyosis , palmoplantar keratoderma , and pachyonychia congenita . On the basis of clinical , morphological , and ultrastructural observations the epidermolysis bullosa group has been divided into three major categories . In epidermolysis bullosa simplex blister formation appears within the basal cell layer of the epidermis , and many mutations have been found in the genes of keratin 5 and 14 which are both expressed in basal keratinocytes . epidermolytic hyperkeratosis leads to an epidermal separation in the suprabasal cell layers . In these patients numerous point mutations have now been described in the suprabasally expressed genes of keratin 1 and 10 . In ichthyosis bullosa of siemens blisters occur in the more upper suprabasal epidermis coincidental with the expression of keratin 2e , and mutations have been detected in the corresponding gene . In epidermolytic palmoplantar hyperkeratosis the suprabasal epidermal splitting is restricted to palms and soles …

The molecular genetics of keratin disorders. (2003 Apr)
The molecular genetics of keratin disorders . keratins are the type I and II intermediate filament proteins which form a cytoskeletal network within all epithelial cells . They are expressed in pairs in a tissue and differentiation specific fashion . epidermolysis bullosa simplex ( EBS ) was the first human disorder to be associated with keratin mutations . The abnormal keratin filament aggregates observed in basal cell keratinocytes of some EBS patients are composed of keratins K5 and K14 . dominant mutations in the genes encoding these proteins were shown to disrupt the keratin filament cytoskeleton resulting in cells that are less resilient and blister with mild physical trauma . identification of mutations in other keratin genes soon followed with attention focussed on disorders showing abnormal clumping of keratin filaments in specific cells . For example , in bullous congenital ichthyosiform erythroderma , clumping of filaments in the suprabasal cells led to the identification of mutations in the suprabasal keratins , K1 and K10 . mutations have now been identified in 18 keratins , all of which produce a fragile cell phenotype . these include ichthyosis bullosa of siemens ( K2e ) , epidermolytic palmoplantar keratoderma ( K1 , K9 ) , pachyonychia congenita ( K6a , K6b , K16 , K17 ) , white sponge nevus ( K4 , K13 ) , meesmann s corneal dystrophy ( K3 , K12 ) , cryptogenic cirrhosis ( K8 , K18 ) and monilethrix ( hHb6 , hHb1 ) . In general …

Human keratin diseases : the increasing spectrum of disease and subtlety of the phenotype genotype correlation. (2000 May)
human keratin diseases : the increasing spectrum of disease and subtlety of the phenotype genotype correlation . keratins are obligate heterodimer proteins that form the intermediate filament cytoskeleton of all epithelial cells . keratins are tissue and differentiation specific and are expressed in pairs of types I and II proteins . The spectrum of inherited human keratin diseases has steadily increased since the causative role of mutations in the basal keratinocyte keratins 5 and 14 in epidermolysis bullosa simplex ( EBS ) was first reported in 1991 . At the time of writing , mutations in 15 epithelial keratins and two trichocyte keratins have been associated with human diseases which include EBS , bullous congenital ichthyosiform erythroderma , epidermolytic palmoplantar keratoderma , ichthyosis bullosa of siemens , diffuse and focal non epidermolytic palmoplantar keratoderma , pachyonychia congenita and monilethrix . mutations in extracutaneous keratins have been reported in oral white sponge naevus and meesmann s corneal dystrophy . New subtleties of phenotype genotype correlation are emerging within the keratin diseases with widely varying clinical presentations attributable to similar mutations within the same keratin . mutations in keratin associated proteins have recently been reported for the first time . This article reviews clinical , ultrastructural and molecular aspects of all the keratin diseases described to date and delineates potential future areas of research in this field .