Three keratin gene mutations account for the majority of dominant simplex epidermolysis bullosa cases within the population of Ireland

Humphries, Marian M.; Mansergh, Fiona C.; Kiang, Anna-Sophie; Jordan, Siobhán A.; Sheils, Denise M.; Martin, Michael; Farrar, G. Jane; Kenna, Paul F.; Young, Melodie; Humphries, Peter

doi:10.1002/(sici)1098-1004(1996)8:1<57::aid-humu8>3.0.co;2-m

Cited by 25 publications

(16 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…All previously reported mutations which cause PC have affected one of the highly conserved sequences at either end of this helical rod domain common to all keratin molecules (Munro, 2001), except a mutation in the midregion of the 2B helical domain of K16 reported by Connors et al (2001) in a patient with delayed-onset PC-1. Interestingly, mutations in the second half of the 1A domain have been associated with other keratin disorders, for example equivalent residue in keratin 5 (K5), N193K (N25K in the 1A domain) causes mild Weber-Cockayne form of epidermolysis bullosa simplex (EBS) (Humphries et al, 1996). In EBS, the site of mutation is a strong determinant of the severity of the phenotype.…”

Section: Discussionmentioning

confidence: 99%

A Novel Mutation in the Second Half of the Keratin 17 1A Domain in a Large Pedigree with Delayed-Onset Pachyonychia Congenita Type 2

Xiao

Yan

Ren

et al. 2004

Journal of Investigative Dermatology

View full text Add to dashboard Cite

Pachyonychia congenita type 2 (PC-2), also known as Jackson-Lawler type PC, is an autosomal dominant disorder characterized by hypertrophic nail dystrophy associated with focal keratoderma and multiple pilosebaceous cysts. We report a large Chinese pedigree of typical delayed-onset PC-2 that includes 19 affected members. Direct sequencing of PCR products revealed a novel heterozygous 325A-->G mutation in the affected members. This mutation predicts the substitution of asparagine by aspartic acid in codon 109 (N109D) located in the second half of the keratin 17 1A domain, where similar mutation in keratin 5 is associated with the mild Weber-Cockayne form of epidermolysis bullosa simplex.

show abstract

Section: Discussionmentioning

confidence: 99%

A Novel Mutation in the Second Half of the Keratin 17 1A Domain in a Large Pedigree with Delayed-Onset Pachyonychia Congenita Type 2

Xiao

Yan

Ren

et al. 2004

Journal of Investigative Dermatology

View full text Add to dashboard Cite

show abstract

“…The EBS-Dowling-Meara mutation p.Ser181Pro is a point mutation (c.541T4C) resulting in a serine to proline substitution in the highly conserved helix initiation motif within the 1A domain of K5 (Shemanko et al, 2000). The missense mutation p.Asn193Lys (due to DNA point mutation c.579C4G) is located in the second half of the helix 1A domain of K5, outside of the highly conserved region (Humphries et al, 1996;Rugg et al, 2007). This mutation has been shown to be associated with milder, siterestricted presentation of EBS (Humphries et al, 1996;Rugg et al, 2007).…”

Section: Inhibition Of K5 Expression By Specific Sirnasmentioning

confidence: 99%

Development of Allele-Specific Therapeutic siRNA for Keratin 5 Mutations in Epidermolysis Bullosa Simplex

Atkinson

McGilligan

Liao

et al. 2011

Journal of Investigative Dermatology

View full text Add to dashboard Cite

Epidermolysis bullosa simplex (EBS) is an incurable, inherited skin-blistering disorder predominantly caused by dominant-negative mutations in the genes encoding keratins K5 or K14. RNA interference, particularly in the form of small interfering RNA (siRNA), offers a potential therapy route for EBS and related keratin disorders by selectively silencing the mutant allele. Here, using a systemic screening system based on a luciferase reporter gene assay, we have developed mutant-specific siRNAs for two independent EBS-causing missense mutations in the K5 gene (p.Ser181Pro and p.Asn193Lys). The specificity of the allele-specific inhibitors identified in the screen was subsequently confirmed at the protein level, where the lead inhibitors were shown to strongly knock down the expression of mutant proteins with negligible effect on wild-type K5 expression. In a cell-based model system, the lead inhibitors were able to significantly reverse the cytoskeletal aggregation phenotype. Overall, this approach shows promise for the treatment of EBS and paves the way for future clinical trials.

show abstract

“…For KRT5, a genomic mutation detection system has already been described (Stephens et al, 1997), as for the KRT14 hotspot domains (Hut et al, 2000). Although most of the EBS mutations could be identified in the mutation hotspots of KRT5 and KRT14, occasionally a mutation is located outside the hotspots (Jonkman et al, 1996;Humphries et al, 1996;Liovic et al, 2001). Upon screening of nine patients, we found two patients, one with EBS-Koebner and the other one with EBS-Weber-Cockayne, both with no detectable mutation in the hotspot domains of KRT5 and KRT14, suggesting a mutation outside the hotspot domains.…”

Section: Introductionmentioning

confidence: 99%

Mutation analysis of the entire keratin 5 and 14 genes in patients with epidermolysis bullosa simplex and identification of novel mutations

et al. 2003

View full text Add to dashboard Cite

Epidermolysis bullosa simplex is a group of blistering skin disorders caused by defects in one of the keratin genes, KRT5 and KRT14. Previously reported KRT5 and KRT14 mutations are clustered in several hotspots, namely the rod ends of the 1A and 2B domains and in the non-helical linker region L12. Therefore, genomic KRT5 and KRT14 mutation analysis was initially limited to these hotspots. In this study we describe the screening of nine EBS patients for mutations in the hotspots. In two patients, with the Koebner and the Weber-Cockayne subtypes of epidermolysis bullosa simplex respectively, we could, however, not identify any mutation in one of the hotspot domains of KRT5 and KRT14. Therefore, it appeared to be necessary to screen the entire genes for mutations. For KRT5, a complete genomic mutation detection system was previously described. We now developed a complete genomic mutation detection system for KRT14. For the amplification of the KRT14 genes, we make use of restriction sites to exempt the keratin 14 pseudogene sequence from polymerase chain reaction amplification. Using the complete genomic mutation detection system for both KRT5 and KRT14, we identified four novel KRT5 mutations (IVS1-1G>C, K404E, A438D, E475K), two of which are outside the KRT5 hotspot domains, and three novel KRT14 mutations (IVS4+1G>A, L408M, L130P).

show abstract

Three keratin gene mutations account for the majority of dominant simplex epidermolysis bullosa cases within the population of Ireland

Cited by 25 publications

References 42 publications

A Novel Mutation in the Second Half of the Keratin 17 1A Domain in a Large Pedigree with Delayed-Onset Pachyonychia Congenita Type 2

A Novel Mutation in the Second Half of the Keratin 17 1A Domain in a Large Pedigree with Delayed-Onset Pachyonychia Congenita Type 2

Development of Allele-Specific Therapeutic siRNA for Keratin 5 Mutations in Epidermolysis Bullosa Simplex

Mutation analysis of the entire keratin 5 and 14 genes in patients with epidermolysis bullosa simplex and identification of novel mutations

Contact Info

Product

Resources

About