Keratin 14 Gene Mutations in Patients with Epidermolysis Bullosa Simplex

Chen, Hua; Bonifas, Jeannette M.; Matsumura, Kunie; Ikeda, Shigaku; Leyden, Wendy A.; Epstein, Ervin

doi:10.1111/1523-1747.ep12323846

Cited by 65 publications

(42 citation statements)

References 38 publications

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“…These two motifs have been referred to as the "rod initiation" and "rod termination" motifs. Not surprisingly, a disproportionate fraction of human diseasecausing mutations in IF proteins are found in these highly conserved motifs (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11).…”

Section: The Intermediate Filament (If)mentioning

confidence: 99%

Characterization of Structural Changes in Vimentin Bearing an Epidermolysis Bullosa Simplex-like Mutation Using Site-directed Spin Labeling and Electron Paramagnetic Resonance

Hess

Budamagunta

Fitzgerald

et al. 2005

Journal of Biological Chemistry

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Mutations in intermediate filament protein genes are responsible for a number of inherited genetic diseases including skin blistering diseases, corneal opacities, and neurological degenerations. Mutation of the arginine (Arg) residue of the highly conserved LNDR motif has been shown to be causative in inherited disorders in at least four different intermediate filament (IF) proteins found in skin, cornea, and the central nervous system. Thus this residue appears to be broadly important to IF assembly and/or function. While the genetic basis for these diseases has been clearly defined, the inability to determine crystal structure for IFs has precluded a determination of how these mutations affect assembly/structure/function of IFs. To investigate the impact of mutation at this site in IFs, we have mutated the LNDR to LNDS in vimentin, a Type III intermediate filament protein, and have examined the impact of this change on assembly using electron paramagnetic resonance. Compared with wild type vimentin, the mutant shows normal formation of the coiled coil dimer, with a slight reduction in the stability of the dimer in rod domain 1. Probing the dimer-dimer interactions shows the formation of normal dimer centered on residue 191 but a failure of dimerization at residue 348 in rod domain 2. These data point toward a specific stage of assembly at which a common disease-causing mutation in IF proteins interrupts assembly.

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Section: The Intermediate Filament (If)mentioning

confidence: 99%

Characterization of Structural Changes in Vimentin Bearing an Epidermolysis Bullosa Simplex-like Mutation Using Site-directed Spin Labeling and Electron Paramagnetic Resonance

Hess

Budamagunta

Fitzgerald

et al. 2005

Journal of Biological Chemistry

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“…9,10 Specifically, EBS-DM mutations occur within the highly conserved α-helical end segments of helix 1A and 2B and induce major defects in keratin filament elongation. 4,6,[11][12][13][14][15][16] In particular, R125C and R125H mutations in K14 account for the majority of EBS-DM cases. 10,11 Mutations in EBS-K are more internal to the α-helical rod domain, 5,[17][18][19][20] whereas mutations in EBS-WC have been found in the non-helical linker (L1-2) region of K5 and K14, and in the H1 head domain of K5.…”

Section: Introductionmentioning

confidence: 99%

“…10,11 Mutations in EBS-K are more internal to the α-helical rod domain, 5,[17][18][19][20] whereas mutations in EBS-WC have been found in the non-helical linker (L1-2) region of K5 and K14, and in the H1 head domain of K5. 12,[21][22][23][24][25][26] Recently, a missense mutation in the non-helical V1 head domain of K5 was identified in patients with EBS with mottled pigmentation. 27,28 We investigated a multigenerational family dominantly affected with EBS-DM for mutations in K5 cDNA.…”

Section: Introductionmentioning

confidence: 99%

Donor splice site mutation in keratin 5 causes in-frame removal of 22 amino acids of H1 and 1A rod domains in Dowling-Meara epidermolysis bullosa simplex

Rugg

Rochat

et al. 1999

Eur J Hum Genet

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Epidermolysis bullosa simplex (EBS) arises from mutations within the keratin 5 and 14 (K5 and K14) genes which alter the integrity of basal keratinocytes cytoskeleton. The majority of these defects are missense mutations in the rod domain, whose locations influence the disease severity. We investigated a large family dominantly affected with the Dowling-Meara form of EBS (EBS-DM). Sequencing of amplified and cloned K5 cDNA from cultured keratinocytes revealed a 66 nucleotide deletion in one allele corresponding to the last 22 amino acid residues encoded by exon 1 (Val164 to Lys185). Sequencing of amplified genomic DNA spanning the mutant region revealed a heterozygous G-to-A transition at + 1 position of the consensus GT donor splice site of intron 1 of K5. This mutation leads to the use of an exonic GT cryptic donor splice site, located 66 nucleotides upstream from the normal donor splice site of intron 1. The corresponding peptide deletion includes the last five amino acids of the H1 head domain and the first 17 amino acids of the conserved amino terminal end of the 1A rod domain, including the first two heptad repeats and the helix initiation peptide. The shortened polypeptide is expressed in cultured keratinocytes at levels which are comparable to the normal K5 protein. This is the first splice site mutation to be reported as a cause of EBS-DM. Owing to the functional importance of the removed region, our data strongly suggest that shortened keratin polypeptide can impair keratin filament assembly in a dominant manner and causes EBS-DM.

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“…The parallels between cultured D-M EBS keratinocytes and keratinocytes transfected with mutant keratin genes had also been noted (Kitajima et al, 1989) genes (Bonifas et al, 1991;Coulombe et al, 1991a;Lane et al, 1992), and that these defects reside at chromosomes 17q12-21 and 12qll-12, i.e., at the loci of the type I and type II keratin gene clusters, respectively (Rosenberg et al, 1988;Bonifas et al, 1991;Chan et al, 1993;1994b). lombe et al, 1991a;Stephens et al, 1993;Chen et al, 1995;Chan et al, 1996). Located within the highly conserved amino end of the K14 rod domain, the arginine codon (CGC) appears to be both a target for methylation and subsequent deamination in the epidermis and also a residue that is essential for filament assembly.…”

mentioning

confidence: 99%

“…Located within the highly conserved amino end of the K14 rod domain, the arginine codon (CGC) appears to be both a target for methylation and subsequent deamination in the epidermis and also a residue that is essential for filament assembly. Although D-M EBS cases tend to have mutations within the highly conserved ends of the rod domain of K5 or K14 (Coulombe et al, 1991a;Lane et al, 1992;Hovnanian et al, 1993;Stephens et al, 1993;Chen et al, 1995;Chan et al, 1996), K EBS cases are Intermediate Filaments and Disease frequently proline residues and are located more centrally within the a-helical rod segments (Bonifas et al, 1991;Dong et al, 1993;Humphries et al, 1993;Yamanishi et al, 1994). Interestingly, in filament assembly and/or gene transfection assays, the Dowling-Meara EBS mutations all produce short filament rodlets, suggesting that the process of filament elongation is compromised (Coulombe et al, 1991a; Letai et al, 1993;Chan et al, 1994).…”

mentioning

confidence: 99%

Keith R. Porter Lecture, 1996. Of mice and men: genetic disorders of the cytoskeleton.

Fuchs

1997

MBoC

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Since the time when I was a postdoctoral fellow under the supervision of Dr. Howard Green, then at the Massachusetts Institute of Technology, I have been interested in understanding the molecular mechanisms underlying growth, differentiation, and development in the mammalian ectoderm. The ectoderm gives rise to epidermal keratinocytes and to neurons, which are the only two cell types of the body that devote most of their protein-synthesizing machinery to developing an elaborate cytoskeletal architecture composed of 10-nm intermediate filaments (IFs). Our interest is in understanding the architecture of the cytoskeleton in keratinocytes and in neurons, and in elucidating how perturbations in this architecture can lead to degenerative diseases of the skin and the nervous system. I will concentrate on the intermediate filament network of the skin and its associated genetic disorders, since this has been a long-standing interest of my laboratory at the University of Chicago.

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Keratin 14 Gene Mutations in Patients with Epidermolysis Bullosa Simplex

Cited by 65 publications

References 38 publications

Characterization of Structural Changes in Vimentin Bearing an Epidermolysis Bullosa Simplex-like Mutation Using Site-directed Spin Labeling and Electron Paramagnetic Resonance

Characterization of Structural Changes in Vimentin Bearing an Epidermolysis Bullosa Simplex-like Mutation Using Site-directed Spin Labeling and Electron Paramagnetic Resonance

Donor splice site mutation in keratin 5 causes in-frame removal of 22 amino acids of H1 and 1A rod domains in Dowling-Meara epidermolysis bullosa simplex

Keith R. Porter Lecture, 1996. Of mice and men: genetic disorders of the cytoskeleton.

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