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

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.