Biallelic GLTP mutations cause nonsyndromic epidermal differentiation disorder via disrupted epidermal glucosylceramide transport
Zeqiao Zhang, Shimiao Huang, Adam Jackson, Elizabeth A Jones, Siddharth Banka, Chao Yang, Sisi Zhao, Kunlun Lv, Sha Peng, Zhimiao Lin, Huijun Wang
Zeqiao Zhang, Shimiao Huang, Adam Jackson, Elizabeth A Jones, Siddharth Banka, Chao Yang, Sisi Zhao, Kunlun Lv, Sha Peng, Zhimiao Lin, Huijun Wang
View: Text | PDF
Research Article Dermatology Genetics Metabolism

Biallelic GLTP mutations cause nonsyndromic epidermal differentiation disorder via disrupted epidermal glucosylceramide transport

Abstract

Ceramides are essential skin lipids for maintaining the mammalian skin permeability barrier, which protects against external stimuli. The precursor of epidermal ceramides, glucosylceramides (GlcCer), is synthesized within granular keratinocytes while its precise cellular transport mechanisms remain poorly characterized. Here, we identified 3 pathogenic variants in the GLTP gene, which encodes glycolipid transfer protein, in 5 unrelated families with nonsyndromic epidermal differentiation disorder presenting with generalized skin scaling. The biallelic GLTP variants resulted in loss of competent GLTP expression. CRISPR/Cas9-generated Gltp-knockout mice exhibited lethal barrier defects, partially recapitulating the clinical features of our patients. We demonstrated that GLTP facilitated GlcCer transport in differentiated keratinocytes, with its deficiency causing impaired GlcCer trafficking and consequent aberrant retention in lysosomes, thereby disrupting lysosome function. The lysosomal dysfunction impaired autophagy flux, resulting in delayed keratinocyte terminal differentiation, which is expected to compromise the skin barrier integrity and ultimately lead to abnormal scaling. Pharmacological inhibition of GlcCer synthesis effectively rescued both autophagy and keratinocyte differentiation defects. Our findings establish GLTP as a novel underlying gene for nonsyndromic epidermal differentiation disorders and unravel its essential role in maintaining skin homeostasis during terminal differentiation by mediating epidermal GlcCer transport.

Authors

Zeqiao Zhang, Shimiao Huang, Adam Jackson, Elizabeth A Jones, Siddharth Banka, Chao Yang, Sisi Zhao, Kunlun Lv, Sha Peng, Zhimiao Lin, Huijun Wang

×

Figure 4

Ultrastructural changes in the epidermis of GLTP-nEDD patients and the Gltp-deficient mice.

Options: View larger image (or click on image) Download as PowerPoint
Ultrastructural changes in the epidermis of GLTP-nEDD patients and the G...
(A) Transmission electron microscopy (TEM) analysis of epidermal ultrastructure in patient (P) skin biopsies and a healthy control (HC). Representative images reveal distinct pathological features in patient corneocytes, including numerous vacuoles (solid white arrowheads) and curved membrane structures (hollow white arrowheads). Keratinocytes within the stratum granulosum exhibit irregular perinuclear accumulations of abnormal membranous and vesicular material (red arrowheads), accompanied by reduced lamellar body counts and disrupted lamellar organization. In contrast, healthy human epidermis demonstrates homogeneous, electron-dense, amorphous keratin substance in the stratum corneum and abundant normally structured lamellar bodies (black asterisks) in the granular layer. (B) TEM of murine epidermis indicates intact intercellular lipid lamellae in corneocytes layers of Gltp+/+ epidermis but absent in the Gltp–/– epidermis. Gltp–/– epidermis displayed numerous vacuoles in corneocytes (solid white arrowheads), curved membrane structures (hollow white arrowheads). In the stratum granulosum, lamellar bodies (red arrows) were reduced in number and display disrupted organization in Gltp–/– mice, contrasting with abundant well-structured lamellar bodies in Gltp+/+ epidermis (black arrows). SC, stratum corneum; SG, stratum granulosum.