Inherited ichthyoses/generalized Mendelian disorders of cornification

Schmuth, Matthias; Martinz, Verena; Janecke, Andreas R.; Fauth, Christine; Schossig, Anna; Zschocke, Johannes; Gruber, Robert

doi:10.1038/ejhg.2012.121

Cited by 81 publications

(67 citation statements)

References 90 publications

(77 reference statements)

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“…Similar findings have been observed in other forms of ichthyosis (27)(28)(29). Also, many cells within the stratum corneum retained a cell nucleus (parakeratosis) (Fig.…”

Section: Lmnb2supporting

confidence: 90%

An Absence of Nuclear Lamins in Keratinocytes Leads to Ichthyosis, Defective Epidermal Barrier Function, and Intrusion of Nuclear Membranes and Endoplasmic Reticulum into the Nuclear Chromatin

Jung

Tatar

et al. 2014

Molecular and Cellular Biology

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d B-type lamins (lamins B1 and B2) have been considered to be essential for many crucial functions in the cell nucleus (e.g., DNA replication and mitotic spindle formation). However, this view has been challenged by the observation that an absence of both B-type lamins in keratinocytes had no effect on cell proliferation or the development of skin and hair. The latter findings raised the possibility that the functions of B-type lamins are subserved by lamins A and C. To explore that idea, we created mice lacking all nuclear lamins in keratinocytes. Those mice developed ichthyosis and a skin barrier defect, which led to death from dehydration within a few days after birth. Microscopy of nuclear-lamin-deficient skin revealed hyperkeratosis and a disordered stratum corneum with an accumulation of neutral lipid droplets; however, BrdU incorporation into keratinocytes was normal. Skin grafting experiments confirmed the stratum corneum abnormalities and normal BrdU uptake. Interestingly, the absence of nuclear lamins in keratinocytes resulted in an interspersion of nuclear/endoplasmic reticulum membranes with the chromatin. Thus, a key function of the nuclear lamina is to serve as a "fence" and prevent the incursion of cytoplasmic organelles into the nuclear chromatin.T he B-type lamins, which are expressed in virtually all cells from the earliest stages of development, have been assumed to play vital functions in the cell nucleus (1-8). Multiple studies contributed to this view. One group found lamin B at sites of DNA replication during S-phase and suggested that it was important for DNA replication (1). Disruption of nuclear lamin organization with a dominant negative lamin B mutant in Xenopus egg extracts inhibited DNA replication (2, 3), mitotic spindle assembly (4), and nuclear envelope assembly in interphase (5). An RNA interference (RNAi) knockdown of lamin B1 and lamin B2 was reported to lead to mitotic arrest and apoptosis (6). Other studies reported that B-type lamins were important for chromatin organization and proper gene expression (7,8).The view that B-type lamins play crucial roles in the cell nucleus likely dampened enthusiasm for testing the importance of B-type lamins in knockout mice. Ultimately, however, Yang et al. (9) created conditional knockout alleles for both Lmnb1 and Lmnb2 and used those alleles to generate keratinocyte-specific Lmnb1 Lmnb2 knockout mice. Remarkably, a complete absence of both lamin B1 and lamin B2 in keratinocytes had no discernible effect on cell growth or the complex developmental programs involved in the formation of the epidermis, hair, and nails. By electron microscopy, the nuclear envelope and heterochromatin distribution appeared normal in Lmnb1 Lmnb2-deficient keratinocytes (9). Similarly, hepatocyte-specific Lmnb1 Lmnb2 knockout mice had normal liver histology and normal liver function tests (10). These studies cast doubt on the notion that B-type lamins are essential for DNA replication and mitosis but did not exclude the possibility that these functions were si...

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“…Similar findings have been observed in other forms of ichthyosis (27)(28)(29). Also, many cells within the stratum corneum retained a cell nucleus (parakeratosis) (Fig.…”

Section: Lmnb2supporting

confidence: 90%

An Absence of Nuclear Lamins in Keratinocytes Leads to Ichthyosis, Defective Epidermal Barrier Function, and Intrusion of Nuclear Membranes and Endoplasmic Reticulum into the Nuclear Chromatin

Jung

Tatar

et al. 2014

Molecular and Cellular Biology

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“…Most of the known ichthyoses are nonsyndromic, and the clinical manifestation is restricted to the skin (Schmuth et al, 2013; Traupe et al, 2014). Among different ichthyosis types, the appearance of the skin is very similar, displaying a dry, thickened, scaly phenotype.…”

Section: Introductionmentioning

confidence: 99%

PNPLA1 Deficiency in Mice and Humans Leads to a Defect in the Synthesis of Omega-O-Acylceramides

Grond

Eichmann

Dubrac

et al. 2017

Journal of Investigative Dermatology

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108

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Mutations in PNPLA1 have been identified as causative for autosomal recessive congenital ichthyosis in humans and dogs. So far, the underlying molecular mechanisms are unknown. In this study, we generated and characterized PNPLA1-deficient mice and found that PNPLA1 is crucial for epidermal sphingolipid synthesis. The absence of functional PNPLA1 in mice impaired the formation of omega-O-acylceramides and led to an accumulation of nonesterified omega-hydroxy-ceramides. As a consequence, PNPLA1-deficient mice lacked a functional corneocyte-bound lipid envelope leading to a severe skin barrier defect and premature death of newborn animals. Functional analyses of differentiated keratinocytes from a patient with mutated PNPLA1 demonstrated an identical defect in omega-O-acylceramide synthesis in human cells, indicating that PNPLA1 function is conserved among mammals and indispensable for normal skin physiology. Notably, topical application of epidermal lipids from wild-type onto Pnpla1-mutant mice promoted rebuilding of the corneocyte-bound lipid envelope, indicating that supplementation of ichthyotic skin with omega-O-acylceramides might be a therapeutic approach for the treatment of skin symptoms in individuals affected by omega-O-acylceramide deficiency.

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“…Long-chain fatty aldehydes are oxidized to fatty acids by the enzyme encoded by the fatty aldehyde dehydrogenase (FALDH) gene [22]. Branched fatty acids are broken down by another enzyme encoded by the phytanoyl-CoA hydroxylase (PHYH) gene [23,24]. The 12R-lipoxygenase (ALOX12B) and the epidermis-type lipoxygenase (ALOXE3) genes encode enzymes catalyzing the conversion of arachidonic acid to 12R-hydroxyeicosatetraenoic acid [25].…”

Section: Genetics Of the Epidermal Barrier And Associated Diseasesmentioning

confidence: 99%

“…Causative variations of the genes linked with abnormal lipid metabolism and transport and, thus consequently epidermal barrier dysfunction, can contribute to the development of clinical variants of the same disease with overlapping symptoms, since ALOX12B, ALOXE3, CYP4F22, NIPAL4, ABCA12 and LIPN mutations are frequently associated with the different clinical forms of autosomal recessive congenital ichthyosis [23,[25][26][27]32]. FALDH mutations result in Sjögren-Larsson syndrome [22].…”

Section: Genetics Of the Epidermal Barrier And Associated Diseasesmentioning

confidence: 99%

Pharmacological Targeting of the Epidermal Barrier

Kemény¹,

Nagy²,

Csoma³

et al. 2016

CPD

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The most important function of the skin is to form a barrier between the body and the external environment. The epidermal barrier prevents transepidermal water loss from the skin, but also serves as a barrier to the entry of harmful environmental allergic, toxic or infectious substances. Inherited defects in the genes encoding the components of the epidermal barrier result in the development of rare genetic disorders, whereas polymorphisms in these genes together with environmental factors cause frequent inflammatory skin diseases, such as atopic dermatitis. In this review, components of the skin-barrier function will be reviewed with special emphasis on how the altered epidermal barrier might be repaired. The different strategies to increase the transdermal penetration of drugs is also discussed.3

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Inherited ichthyoses/generalized Mendelian disorders of cornification

Cited by 81 publications

References 90 publications

An Absence of Nuclear Lamins in Keratinocytes Leads to Ichthyosis, Defective Epidermal Barrier Function, and Intrusion of Nuclear Membranes and Endoplasmic Reticulum into the Nuclear Chromatin

An Absence of Nuclear Lamins in Keratinocytes Leads to Ichthyosis, Defective Epidermal Barrier Function, and Intrusion of Nuclear Membranes and Endoplasmic Reticulum into the Nuclear Chromatin

PNPLA1 Deficiency in Mice and Humans Leads to a Defect in the Synthesis of Omega-O-Acylceramides

Pharmacological Targeting of the Epidermal Barrier

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