Giunta
Fakultäten » Medizinische Fakultät » Kinderspital Zürich: Medizinische Klinik » Stoffwechsel und Molekulare Pädiatrie, Abteilung für » Prof. Dr. Matthias R. Baumgartner » Giunta
Completed research project
| Title / Titel | INFLUENCE OF ZINC ON GENE EXPRESSION, COLLAGEN MATURATION AND PROTEIN SECRETION | ||||||
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| Abstract (PDF, 14 KB) | |||||||
| Summary / Zusammenfassung | We have recently described a novel entity which we have designated “spondylocheiro dysplastic form of EDS (SCD-EDS)” (OMIM 612350) to indicate a generalized skeletal dysplasia involving mainly the spine (spondylo) and striking clinical abnormalities of the hands (cheiro) in addition to the EDS-like features. Our study was based on 6 patients from 2 consanguineous families who showed EDS-like features and radiological findings of a mild skeletal dysplasia. The patients had an increased ratio of total urinary pyridinolines, lysyl pyridinoline / hydroxylysyl pyridinoline, of ~1 as opposed to ~ 6 in EDS VI or ~ 0.2 in controls. Lysyl and prolyl residues of collagens were underhydroxylated despite normal lysyl- and prolyl 4-hydroxylase activities in vitro, and underhydroxylation was a generalized process which occurs along the entire molecule, and is not confined to specific residues as shown by MS of the α1(I)- and α2(I)-chain derived peptides of collagen type I and involved at least collagen types I and II. A genome-wide SNP-scan and sequence analyses identified in all patients a homozygous c.483_491del9 mutation in SLC39A13 that encodes for a membrane-bound zinc transporter SLC39A13 (Zip13). We hypothesize that an increased Zn++ content inside the ER competes with Fe++, a cofactor which is necessary for hydroxylation of lysyl and prolyl residues, and thus explains the biochemical findings. Indeed, Zn++ was found to be an effective competitive inhibitor with respect to Fe++ for prolyl 4-hydroxylase and for lysyl hydroxylase. Proper hydroxylation of collagen lysyl residues is important for functional crosslinks as demonstrated by its deficiency in EDS VI, while 4-hydroxylation of collagen prolyl residues is important for the stability of the triple helix as shown in experimental scurvy. Collagen assembly is complex, requiring for example collagen type V as an essential template for collagen type I deposition, so consequences of underhydroxylation in more collagen gene products than simply types I and II will need to be examined to understand fully the pathogenic mechanism. The aim of our future work is to explain what effect the mutation in SLC39A13 has on Zip13 localization and function, and on zinc homeostasis in the cell. Furthermore, the influence of altered zinc homeostasis on gene expression and protein secretion will be explored. Finally, the study of a knock-out mouse model will add important insight into the understanding of the pathophysiology of the syndrome. |
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| Publications / Publikationen | Giunta C., Elcioglu N. H., Albrecht B., Eich G., Chambaz C., Janecke A. R., Yeowell H., Weis M., Eyre D. R., Kraenzlin M., Steinmann B.: Spondylocheiro dysplastic form of the Ehlers-Danlos syndrome―an autosomal-recessive entity caused by mutations in the zinc transporter gene SLC39A13. Am. J. Hum. Genet. 82: 1290-1305, 2008.Krane S. M.: A New Look at a Rare Old Disease. IBMS BoneKEy. 7: 253-257, 2008. Commentary on: Giunta et al., Am J Hum Genet. 82: 1290-1305, 2008.Olsen B.: A Zn-surprise in Ehlers–Danlos syndrome. Matrix Biology 27: 503–504, 2008. Commentary on: Giunta et al., Am. J. Hum. Genet. 82: 1290-1305, 2008.Kraenzlin M.E., Kraenzlin C.A., Meier C., Giunta C., and Steinmann B.: Evaluation of an automated HPLC system for measurement of urinary collagen crosslinks: effect of age, menopause and metabolic bone diseases. Clin. Chem. 9: 1546-1553, 2008.Eyre D., Shao P., Weis M.A., and Steinmann B.: The kyphoscoliotic type of Ehlers Danlos syndrome (type VI): differential effects on the hydroxylation of lysine in collagens I and II revealed by analysis of cross-linked telopeptides from urine. Mol. Genet. Metab. 76: 211-216, 2002.Steinmann B., Eyre D.R., Shao P.: Urinary pyridinoline cross-links in Ehlers-Danlos syndrome type VI. Am. J. Hum. Genet. 57: 1505-1508, 1995. |
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| Duration of Project / Projektdauer | Oct 2008 to Dec 2010 |