Submission Details

The SLC39A13 gene encodes the zinc transporter 13 (ZIP13), which facilitates the transport of zinc from the Golgi apparatus to the cytosol, thereby regulating cellular zinc homeostasis. The gene was first linked to rare early-onset autosomal recessive spondylocheirodysplastic Ehlers-Danlos syndrome (SCD-EDS) in 2008 by two separate groups (Giunta et al., PMID: 18513683 and Fukada et al., PMID: 18985159). In addition to common EDS symptoms such as thin, soft, velvety skin and hypermobile joints, affected individuals exhibit short stature, platyspondyly, tapering fingers, clubfoot, osteopenia, and abnormal radiological findings, including irregular vertebral endplates, flattened epiphyses, enlarged metaphysis, and short, broad femoral necks. Common craniofacial dysmorphic features are protruding eyes, blue sclera, and downslanting palpebral fissures. Other phenotypes are delayed eruption of permanent teeth or oligodontia, wrinkled palm skin, and thenar atrophy. Some patients were also reported muscle weakness, gait disturbances, and corneal abnormalities, with variability between and within families. Six unique homozygous variants, including three missense, one nonsense, one recurrent small deletion, and one splicing variant, have been identified in fourteen patients from eight families across five publications (PMIDs: 18513683, 18985159, 29593477, 32295219, 36727144). The case-level data from these eight probands provide 7.7 points for genetic evidence. The pathogenic mechanism is loss-of-function, supported by experimental evidence. Phenotypes observed in null knockout (KO) mouse model align with symptoms in affected individuals (PMID: 18985159). Studies on osteoblasts, odontoblasts, and dermal fibroblasts from wildtype and KO mice indicate that ZIP13 is crucial for zinc homeostasis and connective tissue development via the BMP/TGF-beta/SMAD signaling pathway (PMID: 18985159). The amount of endogenous ZIP13 protein in patient dermal fibroblasts was significantly reduced compared to cells derived from a heterozygous parent, and zinc failed to be transported into the cytosolic region (PMID: 23213233). In vitro overexpression of the p.Gly74Asp or p.Phe162_Ala164del variants in 239T or Hela cells results in unstable ZIP13 proteins undergoing VCP-dependent degradation (PMID: 25007800). Additionally, ZIP13 transcript is upregulated by myogenic stimulation in C2C12 mouse myoblasts and human dermal fibroblasts, along with the upregulation of myogenic regulatory factors MyoD and Myogenin. Knockdown of ZIP13 expression impairs myogenic differentiation, as evidenced by undifferentiated cell morphology and decreased MYH expression. In patient-derived stem cells with the p.Gly74Asp variant, MyoD, Myogenin, and MYH mRNA and protein levels are reduced compared to healthy controls. Correcting the p.Gly74Asp variant from homozygous to heterozygous state in patient stem cells using gene editing rescues Myogenin mRNA and protein expression after eight days, suggesting ZIP13's role in myogenic differentiation (PMID: 38609428). In summary, SLC39A13 is definitively associated with autosomal recessive SCD-EDS, as demonstrated in both clinical diagnostic and research settings, and has been upheld over time. This classification was approved by the ClinGen IEM GCEP on October 25th, 2024. (SOP Version 11).