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 …

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 .

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 .

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 …

An autosomal recessive exfoliative ichthyosis with linkage to chromosome 12q13. (2003 Jul)
An autosomal recessive exfoliative ichthyosis with linkage to chromosome 12q13 . A new variant of congenital exfoliative ichthyosis in two related bedouin families is reported . The ichthyosis appeared shortly after birth as a fine peeling of nonerythematous skin on the palms and soles . The prominent well demarcated areas of denuded skin in moist and traumatized regions resembled the mauserung phenomenon of ichthyosis bullosa of siemens ( IBS ) . unlike in IBS , epidermolysis is absent on histological examination . electron microscopy revealed a prominent intercellular oedema and numerous aggregates of keratin filaments in basal keratinocytes . abnormal keratin ( K ) 1 expression was seen in the affected epidermis ; however , all other keratins , including K2e , had a distribution comparable to that seen in normal controls . A maximum two point LOD score of 2 . 53 and multipoint LOD score of 3 . 76 were obtained for marker d12s390 , suggesting linkage to the type II keratin cluster on chromosome 12q13 . sequencing of both the K1 gene , the promotor and the 3 calcium regulatory region did not reveal a mutation . K2e and K5 genes , as well as the genes harboured within the minimal region , such as retinoic acid receptor gamma , sterol O acyltransferase 2 , integrin beta7 and insulin like growth factor binding protein 6 , were also excluded . This combination of clinical , histological , ultrastructural and genetic features has not been previously reported in …