Zinc transporter ZIP13 is involved in myogenic differentiation: establishment of Ehlers– Danlos syndrome spondylodysplastic type 3 induced pluripotent stem cells

Abstract Ehlers–Danlos syndrome spondylodysplastic type 3 (EDSSPD3, OMIM 612350) is an inherited recessive connective tissues disease caused by loss of function of SLC39A13/ZIP13, a zinc transporter belonging to the Slc39a/ZIP family. Patients with EDSSPD3 suffer from impaired development of bone and connective tissues, and muscular hypotonia, or myopathy. However, whether ZIP13 participates in the early differentiation process of these cell types remains unclear. In this study, we investigated the role of ZIP13 in myogenic differentiation using murine myoblast cell line (C2C12) as well as human patient-derived induced pluripotent stem cells (iPSCs). We found that ZIP13 expression was upregulated by myogenic stimulation in C2C12 cells, and its knockdown disrupted myotubular differentiation. Myocytes differentiated from iPSCs of patients with EDSSPD3 (EDSSPD3-iPSCs) exhibited incomplete myogenic differentiation. Moreover, the phenotypic abnormalities of EDSSPD3-iPSC-derived myocytes were corrected by genomic editing of the pathogenic ZIP13 mutation, suggesting the indispensable role of ZIP13 in myogenic differentiation. These results clearly indicate that ZIP13 is required for proper myogenic differentiation and that the study of EDSSPD3-iPSCs may help shed light on the molecular basis underlying various clinical features caused by the loss of ZIP13.