scholarly journals Dominant and Recessive Compound Heterozygous Mutations in Epidermolysis Bullosa Simplex Demonstrate the Role of the Stutter Region in Keratin Intermediate Filament Assembly

2002 ◽  
Vol 277 (26) ◽  
pp. 23670-23674 ◽  
Author(s):  
Kana Yasukawa ◽  
Daisuke Sawamura ◽  
James R. McMillan ◽  
Hideki Nakamura ◽  
Hiroshi Shimizu
Keyword(s):  
Epidermolysis Bullosa ◽  
Intermediate Filament ◽  
Compound Heterozygous ◽  
Epidermolysis Bullosa Simplex ◽  
Filament Assembly ◽  
Compound Heterozygous Mutations

Mutations in the non-helical linker segment L1-2 of keratin 5 in patients with Weber-Cockayne epidermolysis bullosa simplex

1994 ◽  
Vol 107 (4) ◽  
pp. 765-774
Author(s):  
Y.M. Chan ◽  
Q.C. Yu ◽  
J. LeBlanc-Straceski ◽  
A. Christiano ◽  
L. Pulkkinen ◽  
...  
Keyword(s):  
Epidermolysis Bullosa ◽  
Intermediate Filament ◽  
Point Mutations ◽  
Epidermolysis Bullosa Simplex ◽  
Keratin Gene ◽  
Filament Assembly ◽  
Keratin Polypeptides ◽  
Epidermolytic Hyperkeratosis ◽  
Hands And Feet ◽  
Linker Segment

Keratins are the major structural proteins of the epidermis. Analyzing keratin gene sequences, appreciating the switch in keratin gene expression that takes place as epidermal cells commit to terminally differentiate, and elucidating how keratins assemble into 10 nm filaments, have provided the foundation that has led to the discoveries of the genetic bases of two major classes of human skin diseases, epidermolysis bullosa simplex (EBS) and epidermolytic hyperkeratosis (EH). These diseases involve point mutations in either the basal epidermal keratin pair, K5 and K14 (EBS), or the suprabasal pair, K1 and K10 (EH). In severe cases of EBS and EH, mutations are found in the highly conserved ends of the alpha-helical rod domain, regions that, by random mutagenesis, had already been found to be important for 10 nm filament assembly. In order to identify regions of the keratin polypeptides that might be more subtly involved in 10 nm filament assembly and to explore the diversity in mutations within milder cases of these diseases, we have focused on Weber-Cockayne EBS, where mild blistering occurs primarily on the hands and feet in response to mechanical stress. In this report, we show that affected members of two different W-C EBS families have point mutations within 1 residue of each other in the non-helical linker segment of the K5 polypeptide. Genetic linkage analyses, the absence of this mutation in > 150 wild-type alleles and filament assembly studies suggest that these mutations are responsible for the W-C EBS phenotype. These findings provide the best evidence to date that the non-helical linker region in the middle of the keratin polypeptides plays a subtle but significant role in intermediate filament structure and/or intermediate filament cytoskeletal architecture.

scholarly journals Complete Cytolysis and Neonatal Lethality in Keratin 5 Knockout Mice Reveal Its Fundamental Role in Skin Integrity and in Epidermolysis Bullosa Simplex

2001 ◽  
Vol 12 (6) ◽  
pp. 1775-1789 ◽  
Author(s):  
Bettina Peters ◽  
Jutta Kirfel ◽  
Heinrich Büssow ◽  
Miguel Vidal ◽  
Thomas M. Magin
Keyword(s):  
Epidermolysis Bullosa ◽  
Basal Cells ◽  
Epidermolysis Bullosa Simplex ◽  
Keratin 5 ◽  
Neonatal Lethality ◽  
Keratin Filaments ◽  
Wide Range ◽  
Skin Integrity

In human patients, a wide range of mutations in keratin (K) 5 or K14 lead to the blistering skin disorder epidermolysis bullosa simplex. Given that K14 deficiency does not lead to the ablation of a basal cell cytoskeleton because of a compensatory role of K15, we have investigated the requirement for the keratin cytoskeleton in basal cells by inactivating the K5 gene in mice. We report that the K5− / − mice die shortly after birth, lack keratin filaments in the basal epidermis, and are more severely affected than K14− / −mice. In contrast to the K14− / −mice, we detected a strong induction of the wound-healing keratin K6 in the suprabasal epidermis of cytolyzed areas of postnatal K5− / − mice. In addition, K5 and K14 mice differed with respect to tongue lesions. Moreover, we show that in the absence of K5 and other type II keratins, residual K14 and K15 aggregated along hemidesmosomes, demonstrating that individual keratins without a partner are stable in vivo. Our data indicate that K5 may be the natural partner of K15 and K17. We suggest that K5 null mutations may be lethal in human epidermolysis bullosa simplex patients.

scholarly journals Threonine 150 Phosphorylation of Keratin 5 Is Linked to Epidermolysis Bullosa Simplex and Regulates Filament Assembly and Cell Viability

2018 ◽  
Vol 138 (3) ◽  
pp. 627-636 ◽  
Author(s):  
Mugdha Sawant ◽  
Nicole Schwarz ◽  
Reinhard Windoffer ◽  
Thomas M. Magin ◽  
Jan Krieger ◽  
...  
Keyword(s):  
Cell Viability ◽  
Epidermolysis Bullosa ◽  
Epidermolysis Bullosa Simplex ◽  
Keratin 5 ◽  
Filament Assembly

scholarly journals Imbalance of intermediate filament component keratin 14 contributes to increased stress signalling in epidermolysis bullosa simplex

2013 ◽  
Vol 22 (4) ◽  
pp. 292-294 ◽  
Author(s):  
Martin Wagner ◽  
Andrea Trost ◽  
Helmut Hintner ◽  
Johann W. Bauer ◽  
Kamil Onder
Keyword(s):  
Epidermolysis Bullosa ◽  
Intermediate Filament ◽  
Epidermolysis Bullosa Simplex ◽  
Keratin 14 ◽  
Stress Signalling
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