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<p>ZIP8, encoded by <i>SLC39A8</i>, mediates cellular uptake of divalent metal ions, including manganese (Mn). Mutations in <i>SLC39A8</i> cause a congenital disorder of glycosylation (CDG) associated with Mn deficiency (SLC39A8-CDG). Here, we report a novel case of SLC39A8-CDG harboring a previously unreported mutation (p.F206I) in the transmembrane domain 3 (TMD3). The patient showed markedly low serum Mn levels and abnormal glycosylation. To evaluate the functional consequences of this variant, we generated cells expressing hZIP8-F206I. Mn, cadmium, and zinc uptake levels in cells expressing hZIP8-F206I were approximately half of those in cells expressing wild-type hZIP8. The mutant hZIP8 also showed reduced plasma membrane localization. These findings suggest that this previously unreported mutation in TMD3 significantly impairs ZIP8-mediated metal transport, leading to CDG.</p>

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Functional characterization of a novel ZIP8 variant causing impaired manganese homeostasis and congenital disorders of glycosylation

  • 期刊论文

  • 发表日期：

    2026年7月22日

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  • Hitomi Fujishiro,
  • Naoya Morisada,
  • Nao Mitani,
  • Rina Nakayama,
  • Natsuki Goto,
  • Yukina Nishito,
  • Taiho Kambe,
  • Nobuhiko Okamoto,
  • Yoshinao Wada,
  • Yusuke Ishida,
  • Hisato Suzuki,
  • Kandai Nozu,
  • Kenjiro Kosaki,
  • Seiichiro Himeno,
  • Daigo Sumi

摘要

ZIP8, encoded by SLC39A8, mediates cellular uptake of divalent metal ions, including manganese (Mn). Mutations in SLC39A8 cause a congenital disorder of glycosylation (CDG) associated with Mn deficiency (SLC39A8-CDG). Here, we report a novel case of SLC39A8-CDG harboring a previously unreported mutation (p.F206I) in the transmembrane domain 3 (TMD3). The patient showed markedly low serum Mn levels and abnormal glycosylation. To evaluate the functional consequences of this variant, we generated cells expressing hZIP8-F206I. Mn, cadmium, and zinc uptake levels in cells expressing hZIP8-F206I were approximately half of those in cells expressing wild-type hZIP8. The mutant hZIP8 also showed reduced plasma membrane localization. These findings suggest that this previously unreported mutation in TMD3 significantly impairs ZIP8-mediated metal transport, leading to CDG.