Expression of the Keratinocyte Lipid Transporter ABCA12 in Developing and Reconstituted Human Epidermis

Yamanaka, Yasuko; Akiyama, Masashi; Sugiyama-Nakagiri, Yoriko; Sakai, Kaori; Goto, Maki; McMillan, James R.; Ota, Mitsuhito; Sawamura, Daisuke; Shimizu, Hiroshi

doi:10.2353/ajpath.2007.061207

Cited by 34 publications

(26 citation statements)

References 43 publications

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“…We transplanted cultured keratinocytes from patients with HI and succeeded in reconstituting HI skin lesions in immunodeficient mice [Yamanaka et al, 2007]. These reconstructed HI lesions showed similar changes to those observed in HI patients' skin.…”

Section: Animal Modelsmentioning

confidence: 89%

ABCA12 mutations and autosomal recessive congenital ichthyosis: A review of genotype/phenotype correlations and of pathogenetic conceptsa

2010

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Mutations in ABCA12 have been described in autosomal recessive congenital ichthyoses (ARCI) including harlequin ichthyosis (HI), congenital ichthyosiform erythroderma (CIE), and lamellar ichthyosis (LI). HI shows the most severe phenotype. CIE and LI are clinically characterized by fine, whitish scales on a background of erythematous skin, and large, thick, dark scales over the entire body without serious background erythroderma, respectively. To date, a total of 56 ABCA12 mutations have been reported in 66 ARCI families including 48 HI, 10 LI, and 8 CIE families of African, European, Pakistani/Indian, and Japanese origin (online database: http://www.derm-hokudai.jp/ABCA12/). A total of 62.5% of reported ABCA12 mutations are expected to lead to truncated proteins. Most mutations in HI are truncation mutations and homozygous or compound heterozygous truncation mutations always results in HI phenotype. In CIE families, at least one mutation on each allele is typically a missense mutation. Combinations of missense mutations in the first ATPbinding cassette of ABCA12 underlie the LI phenotype. ABCA12 is a keratinocyte lipid transporter associated with lipid transport in lamellar granules, and loss of ABCA12 function leads to a defective lipid barrier in the stratum corneum, resulting in an ichthyotic phenotype. Recent work using mouse models confirmed ABCA12 roles in skin barrier formation.

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Section: Animal Modelsmentioning

confidence: 89%

ABCA12 mutations and autosomal recessive congenital ichthyosis: A review of genotype/phenotype correlations and of pathogenetic conceptsa

2010

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“…Recent studies reveal that mutations in an ATPbinding cassette transport protein, ABCA12, are responsible for abnormal LB formation in Harlequin Ichthyosis [7]. Moreover, the abnormal LB formation in these patients is likely due to a failure to package GlcCer into LB [7,8]. In addition, our recent studies suggest that ELOVL4 function, which is required for VLFA and acylCer formation, is also important for LB formation [4].…”

Section: Steps Required For Barrier Lipid Formationmentioning

confidence: 96%

Omega-O-acylceramide, a lipid essential for mammalian survival

Uchida

Holleran

2008

Journal of Dermatological Science

156

161

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“…This pattern of developmental expression was similar to other keratinization-associated molecules, such as transglutaminase 1 and ABCA12. 15,36,37 To further clarify the functional role of CGI-58 during normal human keratinocyte differentiation, we performed knockdown of CGI-58 expression using an RNAi approach, in which we used short RNA duplexcontaining sequences complementary to CGI-58 mRNA to induce specific inhibition of its expression. CGI-58 knockdown led to reduced expression of all of the keratinocyte differentiation markers examined, ie, involucrin, loricrin, filaggrin, and transglutaminase 1.…”

Section: Abnormalmentioning

confidence: 99%

CGI-58 Is an α/β-Hydrolase within Lipid Transporting Lamellar Granules of Differentiated Keratinocytes

Akiyama

Sakai

Takayama

et al. 2008

The American Journal of Pathology

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CGI-58 is the causative molecule underlying DorfmanChanarin syndrome, a neutral lipid storage disease exhibiting apparent clinical features of ichthyosis. CGI-58, associated with triacylglycerol hydrolysis, has an ␣/␤-hydrolase fold and is also known as the ␣/␤-hydrolase domain-containing protein 5. The purpose of this study was to elucidate the function of CGI-58 and the pathogenic mechanisms of ichthyosis in Dorfman-Chanarin syndrome. Using an anti-CGI-58 antibody, we found CGI-58 to be expressed in the upper epidermis, predominantly in the granular layer cells, as well as in neurons and hepatocytes. Immunoelectron microscopy revealed that CGI-58 was also localized to the lamellar granules (LGs), which are lipid transport and secretion granules found in keratinocytes. CGI-58 expression was markedly reduced in the epidermis of patients with harlequin ichthyosis, demonstrating defective LG formation. In cultured keratinocytes, CGI-58 expression was mildly up-regulated under high Ca 2؉ conditions and markedly up-regulated in three-dimensional, organotypic cultures. In the developing human epidermis, CGI-58 immunostaining was observed at an estimated gestational age of 49 days, and CGI-58 mRNA expression was up-regulated concomitantly with both epidermal stratification and keratinocyte differentiation. CGI-58 knockdown reduced expression of keratinocyte differentiation/keratinization markers in cultured human keratinocytes. Our results indicate that CGI-58 is expressed and packaged into LGs during keratinization and likely plays crucial role(s) in keratinocyte differentiation and LG lipid metabolism, contributing to skin lipid barrier formation. (Am J Pathol

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Expression of the Keratinocyte Lipid Transporter ABCA12 in Developing and Reconstituted Human Epidermis

Cited by 34 publications

References 43 publications

ABCA12 mutations and autosomal recessive congenital ichthyosis: A review of genotype/phenotype correlations and of pathogenetic conceptsa

ABCA12 mutations and autosomal recessive congenital ichthyosis: A review of genotype/phenotype correlations and of pathogenetic conceptsa

Omega-O-acylceramide, a lipid essential for mammalian survival

CGI-58 Is an α/β-Hydrolase within Lipid Transporting Lamellar Granules of Differentiated Keratinocytes

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