Background: Zinc (Zn) is an essential trace element and it is abundant in connective tissues, however biological roles of Zn and its transporters in those tissues and cells remain unknown.
The identification of genes that control susceptibility to testicular germ-cell tumours (TGCTs), the most common cancer affecting young men, has been difficult. In laboratory mice, TGCTs arise from primordial germ cells in only the 129 inbred strains, and susceptibility is under multigenic control. The spontaneously arising mutation Ter (ref. 5) on mouse chromosome 18 (Refs 6,7) increases TGCT frequency on a 129/Sv background. We originally used Ter in genetic crosses to identify loci that control tumorigenesis. A genome scan of tumour-bearing progeny from backcrosses between the 129/Sv-Ter/+ and MOLF/Ei strains provided modest evidence that MOLF-derived alleles on chromosome 19 enhance development of bilateral TGCTs (ref. 9). To obtain independent evidence for linkage to the MOLF chromosome, we made an autosomal chromosome substitution strain (CSS; or 'consomic strain') in which chromosome 19 of 129/Sv+/+ was replaced by its MOLF-derived homologue. The unusually high frequency of TGCTs in this CSS (even in the absence of the Ter mutation) provides evidence confirming the genome survey results, identifies linkage for a naturally occurring strain variant allele that confers susceptibility to TGCTs and illustrates the power of CSSs in complex trait analysis.
Skin is the first area that manifests zinc deficiency. However, the molecular mechanisms by which zinc homeostasis affects skin development remain largely unknown. Here, we show that zinc-regulation transporter-/iron-regulation transporter-like protein 7 (ZIP7) localized to the endoplasmic reticulum plays critical roles in connective tissue development. Mice lacking the Slc39a7/Zip7 gene in collagen 1-expressing tissue exhibited dermal dysplasia. Ablation of ZIP7 in mesenchymal stem cells inhibited cell proliferation thereby preventing proper dermis formation, indicating that ZIP7 is required for dermal development. We also found that mesenchymal stem cells lacking ZIP7 accumulated zinc in the endoplasmic reticulum, which triggered zinc-dependent aggregation and inhibition of protein disulfide isomerase, leading to endoplasmic reticulum dysfunction. These results suggest that ZIP7 is necessary for endoplasmic reticulum function in mesenchymal stem cells and, as such, is essential for dermal development.
We describe oral manifestations in six patients (three females and three males aged 6 to 24 years) with Kabuki syndrome (KS), based on their physical, orthopantomographic, and cephalometric findings. All six patients had a high-arched palate, malocclusion, most commonly unilateral posterior cross-bite (5/6), severe maxillary recession and mid-facial hypoplasia. Other frequently observed oral manifestations included small dental arch and hypodontia. Three patients lacked permanent teeth, mostly the central/lateral incisors. Both tooth size (in primary and permanent teeth) and dental arch (in length and width) tended to be small. We would like to stress that oral care and management is a must for the well-being of KS patients.
Little is known about inherited susceptibility to spontaneous germ cells tumours in humans or other species. The Ter mutation in laboratory mice is novel in that it acts codominantly to reduce germ cell numbers on many inbred strain backgrounds and to enhance dramatically inherited predisposition to spontaneous testicular teratocarcinomas in strain 129 inbred mice. We have adopted a PCR-based, DNA pooling method for mice with 'extreme' phenotypes (small testes versus normal-sized testes) to identify a candidate linkage to the Ter locus. Two independent mapping approaches confirmed this evidence for Ter linkage near D18Mit62 on mouse chromosome 18, and suggest a possible human homologue on chromosome 5q.
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