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UDP-GlcNAc-1-Phosphotransferase Is a Clinically Important Regulator of Human and Mouse Hair Pigmentation

  • Stephan Tiede
    Affiliations
    International Center for Lysosomal Disorders, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    University Children’s Research at Kinder-UKE, Children’s Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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  • Jennifer E. Hundt
    Affiliations
    Lübeck Institute of Experimental Dermatology (LIED), University of Lübeck, Lübeck, Germany
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  • Ralf Paus
    Correspondence
    Correspondence: Ralf Paus, Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, 1600 Northwest 10th Avenue, RMSB 2023A, Miami, Florida 33136, USA.
    Affiliations
    Centre for Dermatology Research, University of Manchester, Manchester, United Kingdom

    The NIHR Biomedical Research Centre, Manchester, United Kingdom

    Dr Phillip Frost Department of Dermatology and Cutaneous Surgery, Miller School of Medicine, University of Miami, Miami, Florida, USA

    Monasterium Laboratory, Münster, Germany
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      UDP-GlcNAc-1-phosphotransferase, a product of two separate genes (GNPTAB, GNPTG), is essential for the sorting and transportation of lysosomal enzymes to lysosomes. GNPTAB gene defects cause extracellular missorting of lysosomal enzymes resulting in lysosomal storage diseases, namely mucolipidosis type II and mucolipidosis type III alpha/beta, which is associated with hair discoloration. Yet, the physiological functions of GNPTAB in the control of hair follicle (HF) pigmentation remain unknown. To elucidate these, we have silenced GNPTAB in organ-cultured human HFs as a human ex vivo model for mucolipidosis type II. GNPTAB silencing profoundly inhibited intrafollicular melanin production, the correct sorting of melanosomes, tyrosinase activity, and HMB45 expression in the HF pigmentary unit and altered HF melanocyte morphology in situ. In isolated primary human HF melanocytes, GNPTAB knockdown significantly reduced melanogenesis, tyrosinase activity, and correct tyrosinase protein sorting as well as POMC expression and caused the expected lysosomal enzyme missorting in vitro. Moreover, transgenic mice overexpressing an inserted missense mutation corresponding to that seen in human mucolipidosis type II and mucolipidosis type III alpha/beta showed significantly reduced HF pigmentation, thus corroborating the in vivo relevance of our ex vivo and in vitro findings in the human system. This identifies GNPTAB as a clinically important enzymatic control of human HF pigmentation, likely by directly controlling tyrosinase sorting and POMC transcription in HF melanocytes.

      Abbreviations:

      HF (hair follicle), MLII (mucolipidosis type II), MLIII (mucolipidosis type III), siRNA (small interfering RNA), TYR (tyrosinase)
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