Novel and recurrent mutations in keratin 1 cause epidermolytic ichthyosis and palmoplantar keratoderma

Smith, Frances J.D.; Kreuser‐Genis, I. M.; Jury, C. S.; Wilson, Neil; Terron‐Kwiatowski, A.; Zamiri, M.

doi:10.1111/ced.13800

Cited by 20 publications

(20 citation statements)

References 8 publications

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“…42,43 KRTs were prevailingly served as intracellular scaffolds, there is also considerable evidence reported that KRT1 exerts crucial functions in an inflammatory network as well as the maintenance of skin integrity in keratinocytes. 44 Here, we first detected that KRT1 was down-regulated in the small intestine after radiation exposure, while VA treatment increased the expression level of KRT1 at gene transcription and translation levels, suggesting that KRT1 may play a role in VA-induced amelioration of radiation injury. In support of this, we validated the hypothesis in vivo and in vitro to specifically down-regulated KRT1.…”

Section: Discussionmentioning

confidence: 77%

Gut commensal derived-valeric acid protects against radiation injuries

et al. 2020

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Background: Hematopoietic and intestinal systems side effects are frequently found in patients who suffered from accidental or medical radiation exposure. In this case, we investigated the effects of gut microbiota produced-valeric acid (VA) on radiation-induced injuries. Methods: Mice were exposed to total body irradiation (TBI) or total abdominal irradiation (TAI) to mimic accidental or clinical scenarios. High-performance liquid chromatography (HPLC) was performed to assess short-chain fatty acids (SCFAs) in fecal pellets. Oral gavage with VA was used to mitigate radiation-induced toxicity. Gross examination was performed to assess tissue injuries of thymus, spleen and small intestine. High-throughput sequencing was used to characterize the gut microbiota profile. Isobaric tags for relative and absolute quantitation (iTRAQ) were performed to analyze the difference of protein profile. Hydrodynamic-based gene delivery assay was performed to silence KRT1 in vivo. Results: VA exerted the most significant radioprotection among the SCFAs. In detail, VA replenishment elevated the survival rate of irradiated mice, protected hematogenic organs, improved gastrointestinal (GI) tract function and intestinal epithelial integrity in irradiated mice. Highthroughput sequencing and iTRAQ showed that oral gavage of VA restored the enteric bacteria taxonomic proportions, reprogrammed the small intestinal protein profile of mice following TAI exposure. Importantly, keratin 1 (KRT1) played a pivotal role in the radioprotection of VA. Conclusions: Our findings provide new insights into gut microbiota-produced VA and underpin that VA might be employed as a therapeutic option to mitigate radiation injury in pre-clinical settings.

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Section: Discussionmentioning

confidence: 77%

Gut commensal derived-valeric acid protects against radiation injuries

et al. 2020

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“…Dominant negative mutations of the genes that encode keratin 1 and 10 ( KRT1 , KRT10 ) cause epidermolytic ichthyosis (EI), previously also known as epidermolytic hyperkeratosis and bullous congenital ichthyosiform erythroderma of Brocq. Palmoplantar keratoderma (PPK) is usually associated with KRT1 mutations [ 1 ]. Mutations of genes that encode keratins, including KRT1 , are mostly missense mutations that affect the helix initiation (1A) and helix termination (2B) motifs, which are highly conserved regions of approximately 20 amino acids at the beginning and end of the central helical coiled-coil rod domain [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

Visualization of Keratin with Diffuse Reflectance and Autofluorescence Imaging and Nonlinear Optical Microscopy in a Rare Keratinopathic Ichthyosis

Anker

Fésűs

Kiss

et al. 2021

Sensors

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Keratins are one of the main fluorophores of the skin. Keratinization disorders can lead to alterations in the optical properties of the skin. We set out to investigate a rare form of keratinopathic ichthyosis caused by KRT1 mutation with two different optical imaging methods. We used a newly developed light emitting diode (LED) based device to analyze autofluorescence signal at 405 nm excitation and diffuse reflectance at 526 nm in vivo. Mean autofluorescence intensity of the hyperkeratotic palmar skin was markedly higher in comparison to the healthy control (162.35 vs. 51.14). To further assess the skin status, we examined samples from affected skin areas ex vivo by nonlinear optical microscopy. Two-photon excited fluorescence and second-harmonic generation can visualize epidermal keratin and dermal collagen, respectively. We were able to visualize the structure of the epidermis and other skin changes caused by abnormal keratin formation. Taken together, we were able to show that such imaging modalities are useful for the diagnosis and follow-up of keratinopathic diseases.

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“…Keratin 1 (K1) -keratin 10 (K10) heterodimer is a hallmarker for keratinocyte differentiation [16]. K1 mutations are also associated with inherited skin diseases including epidermolytic ichthyosis, palmar-plantar keratoderma, and ichthyosis with confetti [6,13,14]. Several keratins, including K5, K7, K8/K18, K19, and K20, are of significance for immunohistochemical diagnosis of carcinomas [9].…”

Section: Introductionmentioning

confidence: 99%

A Mild Keratin 1 Decrease Leads to Cell Death and Increased Oxidative Stress in B16-F10 Melanoma Cell Lines

Zhang

Ying

2020

Preprint

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Keratins play multiple significant biological roles in epithelium. K1 / keratin 10 (K10) heterodimer is a hallmarker for keratinocyte differentiation. While keratins are absent in normal melanocyte, keratins have been found in both melanoma cell lines and human melanoma. The biological significance of the keratins in melanoma cells has remained unclear. In our current study we applied K1 siRNA to investigate the biological significance of the K1 in B16-F10 melanoma cells. We found that as low as a 16% decrease in the K1 level led to significant increases in both apoptosis and necrosis of the cells. Moreover, the mild K1 decrease led to significant increases in both dichlorofluorescein (DCF) and ethidium signals -two indicators of oxidative stress -in the cells. Collectively, our findings have provided the first evidence indicating both a critical role of the K1 in maintaining the survival of melanoma cells and an important role of the K1 in modulating the oxidative stress state of the cells. These findings have exposed new functions of keratins in cancer cells, suggesting that K1 may become a novel therapeutic target for melanoma.

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Novel and recurrent mutations in keratin 1 cause epidermolytic ichthyosis and palmoplantar keratoderma

Abstract: Novel and recurrent mutations in keratin 1 F. J. D. Smith et al.

Cited by 20 publications

References 8 publications

Gut commensal derived-valeric acid protects against radiation injuries

Gut commensal derived-valeric acid protects against radiation injuries

Visualization of Keratin with Diffuse Reflectance and Autofluorescence Imaging and Nonlinear Optical Microscopy in a Rare Keratinopathic Ichthyosis

A Mild Keratin 1 Decrease Leads to Cell Death and Increased Oxidative Stress in B16-F10 Melanoma Cell Lines

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