Cloning of multiple keratin 16 genes facilitates prenatal diagnosis of pachyonychia congenita type 1

Smith, Frances J.D.; McKusick, Victor A.; Nielsen, Karl; Pfendner, Ellen G; Uitto, Jouni; McLean, W.H. Irwin

doi:10.1002/(sici)1097-0223(199910)19:10<941::aid-pd663>3.0.co;2-w

Cited by 41 publications

(25 citation statements)

References 31 publications

(43 reference statements)

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“…The mutation p.Ser128Pro affects the 13th amino acid residue of the KRT14-1A domain, a region termed the helix initiation motif where serine is highly conserved within the family of type I keratins and where most EBS-DM mutations are located. No substitutions of serine residue at this position have been described in type I keratins, but its deletion was observed in KRT16 causing type 1 pachyonychia congenita 40 and in KRT17 causing type 2 pachyonychia congenita. 41 Another mutation localized in the 1A domain of KRT14 was p.Leu136Pro.…”

Section: Discussionmentioning

confidence: 99%

Keratin mutations in patients with epidermolysis bullosa simplex: correlations between phenotype severity and disturbance of intermediate filament molecular structure

Jeřábková

Marek

Bučková

et al. 2010

British Journal of Dermatology

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Section: Discussionmentioning

confidence: 99%

Keratin mutations in patients with epidermolysis bullosa simplex: correlations between phenotype severity and disturbance of intermediate filament molecular structure

Jeřábková

Marek

Bučková

et al. 2010

British Journal of Dermatology

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“…Knowledge of the exact gene defect allows for better genetic counseling and in cases of severe PC, if requested, the option of prenatal diagnosis. When the familial mutation is known, this can be performed at an early stage of pregnancy by chorionic villus biopsy, as we have previously demonstrated (Smith et al, 1999b). In addition, knowing the molecular basis of PC will undoubtedly help in the rational design of novel gene-based or drug-based therapies for these conditions, which remain incurable at this time.…”

Section: Discussionmentioning

confidence: 99%

“…Many of these are processed, intron-less pseuodogenes, notably those related to the simple epithelial keratin genes K8 and K18, for which there are nearly 150 pseudogenes in the human genome (Hesse et al, 2001). Other keratins have conventional intron-containing pseudogenes, in particular the keratins involved in PC, namely K6, K16, and K17 (Troyanovsky et al, 1992;Takahashi et al, 1995;Smith et al, 1999b). The presence of pseudogenes whose sequences are highly homologous to the functional gene, makes genetic analysis difficult using genomic DNA, as discussed below.…”

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confidence: 91%

The Genetic Basis of Pachyonychia Congenita

Smith

Liao

Cassidy

et al. 2005

Journal of Investigative Dermatology Symposium Proceedings

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In 1994, the molecular basis of pachyonychia congenita (PC) was elucidated. Four keratin genes are associated with the major subtypes of PC: K6a or K16 defects cause PC-1; and mutations in K6b or K17 cause PC-2. Mutations in keratins, the epithelial-specific intermediate filament proteins, result in aberrant cytoskeletal networks which present clinically as a variety of epithelial fragility phenotypes. To date, mutations in 20 keratin genes are associated with human disorders. Here, we review the genetic basis of PC and report 30 new PC mutations. Of these, 25 mutations were found in PC-1 families and five mutations were identified in PC-2 kindreds. All mutations identified were heterozygous amino acid substitutions or small in-frame deletion mutations with the exception of an unusual mutation in a sporadic case of PC-1. The latter carried a 117 bp duplication resulting in a 39 amino acid insertion in the 2B domain of K6a. Also of note was mutation L388P in K17, which is the first genetic defect identified in the helix termination motif of this protein. Understanding the genetic basis of these disorders allows better counseling for patients and paves the way for therapy development.

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“…A remarkable feature of K6 is that there have been descriptions of multiple functional K6 genes in several mammals; humans may have seven active K6 genes (43,46), bovines may have up to three (5,27), and mice have at least two (38,44). In contrast to this, the assumed type I partners of K6, K16 and K17, appear to have only one functional gene and several pseudogenes (39,45). While K6, K16, and K17 share the characteristic inducible expression in response to perturbations of epidermal homeostasis, their constitutive expression patterns are not identical.…”

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confidence: 99%

Delayed Wound Healing in Keratin 6a Knockout Mice

Wojcik¹,

Bundman²,

Roop

2000

Molecular and Cellular Biology

143

115

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Keratin 6 (K6) expression in the epidermis has two components: constitutive expression in the innermost layer of the outer root sheath (ORS) of hair follicles and inducible expression in the interfollicular epidermis in response to stressful stimuli such as wounding. Mice express two K6 isoforms, MK6a and MK6b. To gain insight into the functional significance of these isoforms, we generated MK6a-deficient mice through mouse embryonic stem cell technology. Upon wounding, MK6a was induced in the outer ORS and the interfollicular epidermis including the basal cell layer of MK6a ؉/؉ mice, whereas MK6b induction in MK6a ؊/؊ mice was restricted to the suprabasal layers of the epidermis. After superficial wounding of the epidermis by tape stripping, MK6a ؊/؊ mice showed a delay in reepithelialization from the hair follicle. However, the healing of full-thickness skin wounds was not impaired in MK6a ؊/؊ animals. Migration and proliferation of MK6a ؊/؊ keratinocytes were not impaired in vitro. Furthermore, the migrating and the proliferating keratinocytes of full-thickness wounds in MK6a ؊/؊ animals expressed neither MK6a nor MK6b. These data indicate that MK6a does not play a major role in keratinocyte proliferation or migration but point to a role in the activation of follicular keratinocytes after wounding. This study represents the first report of a keratin null mutation that results in a wound healing defect.

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Cloning of multiple keratin 16 genes facilitates prenatal diagnosis of pachyonychia congenita type 1

Cited by 41 publications

References 31 publications

Keratin mutations in patients with epidermolysis bullosa simplex: correlations between phenotype severity and disturbance of intermediate filament molecular structure

Keratin mutations in patients with epidermolysis bullosa simplex: correlations between phenotype severity and disturbance of intermediate filament molecular structure

The Genetic Basis of Pachyonychia Congenita

Delayed Wound Healing in Keratin 6a Knockout Mice

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