ABSTRACT
Ehlers-Danlos syndrome spondylodysplastic type 3 (EDSSPD3, OMIM 612350) is an inherited recessive connective tissue disorder that is caused by loss of function of SLC39A13/ZIP13, a zinc transporter belonging to the Slc39a/ZIP family. We previously reported that patients with EDSSPD3 harboring a homozygous loss of function mutation (c.221G > A, p.G64D) in ZIP13 exon 2 (ZIP13G64D) suffer from impaired development of bone and connective tissues, and muscular hypotonia. However, whether ZIP13 participates in the early differentiation of these cell types remains unclear. In the present study, we investigated the role of ZIP13 in myogenic differentiation using a murine myoblast cell line (C2C12) as well as patient-derived induced pluripotent stem cells (iPSCs). We found that ZIP13 gene expression was upregulated by myogenic stimulation in C2C12 cells, and its knockdown disrupted myotubular differentiation. Myocytes differentiated from iPSCs derived from patients with EDSSPD3 (EDSSPD3-iPSCs) also exhibited incomplete myogenic differentiation. Such phenotypic abnormalities of EDSSPD3-iPSC-derived myocytes were corrected by genomic editing of the pathogenic ZIP13G64D mutation. Collectively, our findings suggest the possible involvement of ZIP13 in myogenic differentiation, and that EDSSPD3-iPSCs established herein may be a promising tool to study the molecular basis underlying the clinical features caused by loss of ZIP13 function.
Subject(s)
Carrier Proteins , Ehlers-Danlos Syndrome , Osteochondrodysplasias , Animals , Humans , Mice , Cell Differentiation/geneticsABSTRACT
OBJECTIVE: The purpose of the study was to evaluate the hypothesis that patients having a vasovagal reaction (VVR) after blood vessel puncture show increased FDG accumulation in bilateral adrenal glands. METHODS: Over the past 8 years, 26 patients experienced a VVR after blood vessel puncture following intra-venous injection of FDG at our institution. Of the 26 patients, 16 underwent multiple-occasion FDG-PET/CT scans while suffering a VVR at only one examination. All 16 patients had no morphological abnormality in the adrenal glands on FDG-PET/CT and follow-up examination. For the 16, we retrospectively reviewed the FDG-PET/CT scan with respect to the adrenal glands and compared the result to that for the FDG-PET/CT scan of the same patient when there was no VVR event. We used both visual analysis and semi-quantitative analysis employing either maximum standardized uptake value (SUVmax) or adrenal-to-liver (A/L) SUVmax ratio. RESULTS: On visual analysis of the FDG-PET/CT with VVR, accumulations in both of the adrenal glands was judged positive, defined as higher than the hepatic accumulation, in 84 % of the cases. The SUVmax in the right adrenal gland was 2.79 ± 0.69 with VVR and 1.92 ± 0.33 without VVR; this value in the left adrenal gland was 3.07 ± 0.71 with VVR and 2.05 ± 0.39 without. Mean SUVmax of both adrenal glands was 2.93 ± 0.66 with VVR and 1.98 ± 0.35 without. The A/L SUVmax ratio in the right adrenal gland was 1.02 ± 0.26 with VVR and 0.69 ± 0.11 without; this value in the left was 1.11 ± 0.23 with VVR and 0.74 ± 0.15 without. The mean A/L SUVmax ratio of both adrenal glands was 1.06 ± 0.24 with VVR and 0.72 ± 0.13 without. Each parameter with VVR was significantly higher than that without. For the two adrenal glands, the mean SUVmax with VVR was 48 % higher than that without VVR. CONCLUSIONS: We confirmed the hypothesis that patients having a VVR after blood vessel puncture show increased FDG accumulation in their bilateral adrenal glands. This may reflect hyper-metabolism of the adrenal glands in synthesizing and secreting catecholamine.
