Disease relevance of KRT2

• Unlike normal and psoriatic skin, K2e expression in hypertrophic and keloid scars began in the deepest suprabasal layer [1].
• In cutaneous basal and squamous cell carcinomas, K2e was absent in most tumor islands but the overlying epidermis showed strong expression [1].
• The normal expression of K2e in the upper spinous and granular layers of interfollicular epidermis is increased in keloid scars but showed distinct down-regulation in psoriasis and hypertrophic scars where keratinocytes are known to undergo activation [1].
• 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 [2].
• Mutations in the K2e gene cause epidermolytic hyperkeratosis confined to the upper spinous and granular layers, as observed in IBS [3].

High impact information on KRT2

• 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 [4].
• Here we report the influence of keratinocyte activation, proliferation, and keratinization on K2e expression in samples of cutaneous and oral lesions [1].
• No significant K2e expression in nonkeratinized or keratinized oral epithelia, including buccal mucosa, lateral border of tongue and gingiva was detected [1].
• Blockage of nicotinic (n)AChR with mecamylamine led to a less pronounced delay in epidermal differentiation and proliferation than blockage of muscarinic (m)AChR with atropine, evidenced by reduced epithelial thickness and expression of terminal differentiation markers like cytokeratin 2e or filaggrin [5].
• Recently, mutations in the helix initiation or termination motifs of keratin 2e (KRT2E) have been described in ichthyosis bullosa of Siemens patients [6].

Biological context of KRT2

• Taken together, the data suggest that K2e expression in skin is sensitive to keratinocyte activation but its up-regulation in oral lesions is a reflection of the degree of orthokeratinization [1].
• 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 [7].
• Here, we have determined the genomic organization and complete sequence of the KRT2E gene, which consists of nine exons, spanning 7634 bp of DNA [2].
• IBS has been linked to the type II keratin cluster on chromosome 12q, and K2e mutations have recently been identified in IBS patients [8].
• We have studied genomic DNA from two IBS families and in both cases heterozygous point mutations were found in the 2B helical domain of K2e [8].

Anatomical context of KRT2

• Epidermal sheets from 14 weeks EGA showed that K2e + cells were excluded from developing hair follicles [9].
• K2e was excluded from developing sweat glands and ducts and from developing hair follicles at the hair germ and early peg stages [9].
• By 15 weeks EGA in the fetal hair follicle small groups of cells were K2e + and by 19 weeks K2e + cells were seen at the level of the matrix [9].

Associations of KRT2 with chemical compounds

• This mutation results in substitution of the codon for glutamic acid by a codon for lysine in position 493 in K2e (E493K) [10].

Other interactions of KRT2

• Previous studies have shown that these genodermatoses are due to mutations in the KRT1 and KRT2E genes, respectively [7].
• Part of the K2e gene was amplified by polymerase chain reaction using genomic DNA from affected and unaffected individuals from two IBS families [11].

Analytical, diagnostic and therapeutic context of KRT2

• 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 [11].
• Sequence analysis revealed the presence of mutations in the K2e gene in patients with ichthyosis bullosa of Siemens [12].
• By in situ hybridization and immunocytochemistry, we further show that both CK 2e and CK 2p are expressed only in suprabasal cell layers of the specific epithelia where they can accumulate to represent major cytoskeletal proteins [13].

References