Development of ichthyosiform skin compensates for defective permeability barrier function in mice lacking transglutaminase 1

Kuramoto, Nobuyuki; Tajima, Toshihiro; Takami, Takeshi; Matsuki, Masato; Morioka, Hiroyuki; Robinson, John M.; Yamanishi, Kiyofumi

doi:10.1172/jci200213563

Cited by 31 publications

(33 citation statements)

References 43 publications

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“…The massive hyperkeratosis associated with a thickened stratum corneum observed here was also described in transglutaminase 1 knockout mice, which have a defective skin barrier (24). Indeed, many diseases that affect skin permeability result in a thickening of the stratum corneum and scaling as a protective mechanism (25).…”

Section: Fatp4supporting

confidence: 64%

Cloning of wrinkle-free, a previously uncharacterized mouse mutation, reveals crucial roles for fatty acid transport protein 4 in skin and hair development

Moulson

Martin

Lugus

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

111

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Wrinkle-free (wrfr) is a previously uncharacterized, spontaneous, autosomal recessive mouse mutation resulting in very tight, thick skin. wrfr mutant mice exhibit severe breathing difficulties secondary to their tight skin and die shortly after birth. This phenotype is strikingly similar to a very rare human genetic disorder, restrictive dermopathy. wrfr mutant mice display a defective skin barrier, which is normally imparted by the cornified envelope, a composite of protein and lipid that prevents loss of water from within and entry of potentially harmful substances from without. In addition, hair growth from grafted wrfr skin is impaired. Positional cloning of the wrfr mutation revealed a retrotransposon insertion into a coding exon of Slc27a4, the gene encoding fatty acid transport protein (FATP)4. FATP4 is the primary intestinal FATP and is thought to play a major role in dietary fatty acid uptake; it therefore is viewed as a target to prevent or reverse obesity. However, its function in vivo had not been determined. Our results demonstrate an unexpected yet critical role for FATP4 in skin and hair development and suggest Slc27a4 to be a candidate gene for restrictive dermopathy.T he skin of mammals is composed of a dermis and an epidermis separated by a basement membrane. The epidermis is stratified, consisting of basal keratinocyte, spinous͞ prickle, granular, and squamous͞cornified layers. Keratinocytes move upward from the basement membrane and progress through a scheduled program of differentiation, with cell death marking their final differentiation step. During this differentiation program, keratinocytes flatten and accumulate lipids that are discharged into the intercellular space (1). In the stratum corneum the lipids are crosslinked with a number of proteins including loricrin and involucrin to form the cornified envelope (2). The insoluble cornified envelope is a composite of protein and lipid that serves as a barrier to loss of water from within and to entry of potentially harmful substances from without. Without such a barrier, life on land could not exist (3).We discovered a spontaneous, autosomal recessive mutation in our mouse colony causing extremely tight, thick skin. We named the mutation wrinkle-free (wrfr). The wrfr phenotype is similar to a rare human disease called restrictive dermopathy (4, 5). Newborn wrfr Ϫ͞Ϫ mice have difficulty breathing because of the tight skin, do not suckle, exhibit a defective skin barrier, and die several hours after birth. There are also defects in hair follicle morphogenesis and hair growth. Because of the presumed fundamental importance of the mutated gene to skin development and its potential relevance to human disease, we sought to identify the affected gene. Here we present a characterization of the wrfr phenotype and the positional cloning of the wrfr mutation. Materials and MethodsMicrosatellite Marker Analysis. Genomic DNA was prepared from tissues by standard proteinase K digestion, phenol͞chloroform extraction, and ethanol precipitation (6) or by ...

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Section: Fatp4supporting

confidence: 64%

Cloning of wrinkle-free, a previously uncharacterized mouse mutation, reveals crucial roles for fatty acid transport protein 4 in skin and hair development

Moulson

Martin

Lugus

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

111

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“…Indeed, transepidermal water loss in newborn wild-type mice was 0.06 mg/cm 2 /h Ϯ 0.01 (n ϭ 3), whereas it was 0.24 mg/cm 2 /h in a single Dgat2 Ϫ/Ϫ newborn, indicative of impaired permeability barrier function in the latter (31, 32). The barrier abnormality in Dgat2 Ϫ/Ϫ mice was also demonstrated by increased permeation of toluidine blue dye (33) (Fig. 9b).…”

Section: Dgat2 Is Essential For Permeability Barrier Function Of the mentioning

confidence: 80%

Lipopenia and Skin Barrier Abnormalities in DGAT2-deficient Mice

Stone

Myers

Watkins³

et al. 2004

Journal of Biological Chemistry

530

484

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The synthesis of triglycerides is catalyzed by two known acyl-CoA:diacylglycerol acyltransferase (DGAT) enzymes. Although they catalyze the same biochemical reaction, these enzymes share no sequence homology, and their relative functions are poorly understood. Gene knockout studies in mice have revealed that DGAT1 contributes to triglyceride synthesis in tissues and plays an important role in regulating energy metabolism but is not essential for life. Here we show that DGAT2 plays a fundamental role in mammalian triglyceride synthesis and is required for survival. DGAT2-deficient (Dgat2 ؊/؊ ) mice are lipopenic and die soon after birth, apparently from profound reductions in substrates for energy metabolism and from impaired permeability barrier function in the skin. DGAT1 was unable to compensate for the absence of DGAT2, supporting the hypothesis that the two enzymes play fundamentally different roles in mammalian triglyceride metabolism.Triglycerides (triacylglycerols) are the major storage form of energy in eukaryotic organisms. However, excessive deposition of triglycerides in white adipose tissue (WAT) 1 leads to obesity and in non-adipose tissues (such as pancreatic ␤ cells, skeletal muscle, and liver) is associated with tissue dysfunction referred to as lipotoxicity (1, 2). Therefore, an understanding of the processes that mediate triglyceride synthesis is of significant biomedical importance.Triglycerides are synthesized from diacylglycerol and activated forms of fatty acids (fatty acyl-CoAs) in a reaction catalyzed by acyl-CoA:diacylglycerol acyltransferase (DGAT) enzymes (3-5). The genes for two DGAT enzymes, DGAT1 and DGAT2, have been identified (6, 7). Both DGAT1 and DGAT2 are ubiquitously expressed, with the highest levels of expression found in tissues that are active in triglyceride synthesis, such as WAT, small intestine, liver, and mammary gland (6, 7). Both enzymes are intrinsic membrane proteins, although DGAT1 has 6 -12 putative transmembrane domains, whereas DGAT2 has one. Both also have similarly broad fatty acyl-CoA substrate specificities in in vitro assays (7). However, despite their ability to catalyze similar reactions, DGAT1 and DGAT2 belong to different gene families that share neither DNA nor protein sequence similarity. DGAT1 is homologous to the acylCoA:cholesterol acyltransferase enzymes, ACAT1 and ACAT2, which are involved in cholesterol ester biosynthesis (6), whereas DGAT2 shares homology with acyl-CoA:monoacylglycerol acyltransferase enzymes (8 -13). This raises the question of why two different types of DGAT enzymes have emerged from convergent evolution.Insights into the functions of DGAT1 and DGAT2 in triglyceride metabolism have been provided by studies in yeast. Through deletion and overexpression studies, several groups have demonstrated that DGA1, the yeast homologue of DGAT2, is the major DGAT enzyme contributing to triglyceride synthesis and storage in yeast (14 -16). In contrast, ARE2, a yeast homologue of DGAT1, plays a minor role in triglyceride synthesis. Intere...

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“…Cornified cell envelope formation is essential as the scaffold upon which normal intercellular lipid layer formation in the stratum corneum can then take place [25]. Mutations in the transglutaminase 1 gene (TGM1) cause defects in the intercellular lipid layers in the stratum corneum leading to defective barrier function of the stratum corneum resulting in the ichthyosis phenotype seen in LI patients [25] and in transglutaminase 1 knockout mice [26]. It remains to be clarified to what extent a defective cornified cell envelope alone contributes to the barrier abnormality in these conditions.…”

Section: Defective Intercellular Lipid Is the Main Idea Behind The Pamentioning

confidence: 99%

Harlequin ichthyosis and other autosomal recessive congenital ichthyoses: The underlying genetic defects and pathomechanisms

Akiyama

2006

Journal of Dermatological Science

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Development of ichthyosiform skin compensates for defective permeability barrier function in mice lacking transglutaminase 1

Cited by 31 publications

References 43 publications

Cloning of wrinkle-free, a previously uncharacterized mouse mutation, reveals crucial roles for fatty acid transport protein 4 in skin and hair development

Cloning of wrinkle-free, a previously uncharacterized mouse mutation, reveals crucial roles for fatty acid transport protein 4 in skin and hair development

Lipopenia and Skin Barrier Abnormalities in DGAT2-deficient Mice

Harlequin ichthyosis and other autosomal recessive congenital ichthyoses: The underlying genetic defects and pathomechanisms

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