Spondylocheiro Dysplastic Form of the Ehlers-Danlos Syndrome—An Autosomal-Recessive Entity Caused by Mutations in the Zinc Transporter Gene SLC39A13

Division of Metabolism and Molecular Pediatrics, University Children's Hospital, CH-8032 Zurich, Switzerland.
The American Journal of Human Genetics (Impact Factor: 10.93). 07/2008; 82(6):1290-305. DOI: 10.1016/j.ajhg.2008.05.001
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We present clinical, radiological, biochemical, and genetic findings on six patients from two consanguineous families that show EDS-like features and radiological findings of a mild skeletal dysplasia. The EDS-like findings comprise hyperelastic, thin, and bruisable skin, hypermobility of the small joints with a tendency to contractures, protuberant eyes with bluish sclerae, hands with finely wrinkled palms, atrophy of the thenar muscles, and tapering fingers. The skeletal dysplasia comprises platyspondyly with moderate short stature, osteopenia, and widened metaphyses. Patients have an increased ratio of total urinary pyridinolines, lysyl pyridinoline/hydroxylysyl pyridinoline (LP/HP), of approximately 1 as opposed to approximately 6 in EDS VI or approximately 0.2 in controls. Lysyl and prolyl residues of collagens were underhydroxylated despite normal lysyl hydroxylase and prolyl 4-hydroxylase activities; underhydroxylation was a generalized process as shown by mass spectrometry of the alpha1(I)- and alpha2(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_491 del9 SLC39A13 mutation that encodes for a membrane-bound zinc transporter SLC39A13. We hypothesize that an increased Zn(2+) content inside the endoplasmic reticulum competes with Fe(2+), a cofactor that is necessary for hydroxylation of lysyl and prolyl residues, and thus explains the biochemical findings. These data suggest an entity that we have designated "spondylocheiro dysplastic form of EDS (SCD-EDS)" 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.

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    • "), was also reported in human SCD-EDS patients (Giunta et al, 2008). Characterization of the wild-type (WT) ZIP13 protein revealed that it is localized to the Golgi, possesses 8 putative transmembrane domains (TMs) with luminal N-and C-termini, and forms homo-dimers (Fukada et al, 2008; Bin et al, 2011), and its luminal loop was proposed to be responsible for Zn selection (Potocki et al, 2013). "
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    ABSTRACT: The zinc transporter protein ZIP13 plays critical roles in bone, tooth, and connective tissue development, and its dysfunction is responsible for the spondylocheirodysplastic form of Ehlers-Danlos syndrome (SCD-EDS, OMIM 612350). Here, we report the molecular pathogenic mechanism of SCD-EDS caused by two different mutant ZIP13 proteins found in human patients: ZIP13G64D, in which Gly at amino acid position 64 is replaced by Asp, and ZIP13ΔFLA, which contains a deletion of Phe-Leu-Ala. We demonstrated that both the ZIP13G64D and ZIP13ΔFLA protein levels are decreased by degradation via the valosin-containing protein (VCP)-linked ubiquitin proteasome pathway. The inhibition of degradation pathways rescued the protein expression levels, resulting in improved intracellular Zn homeostasis. Our findings uncover the pathogenic mechanisms elicited by mutant ZIP13 proteins. Further elucidation of these degradation processes may lead to novel therapeutic targets for SCD-EDS.
    EMBO Molecular Medicine 07/2014; 6(8). DOI:10.15252/emmm.201303809 · 8.67 Impact Factor
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    • "Other disorders characterised by blue sclera and potential corneal fragility that may occasionally enter the differential diagnosis of BCS include the spondylocheirodysplastic form of EDS (SCD-EDS) (OMIM: 612350) [20,21], osteogenesis imperfecta (OI; OMIM: 166200) and Marfan syndrome (OMIM: 154700) [13]. Blue sclerae were a feature of SCD-EDS in the 3 families reported to date with this condition. "
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    ABSTRACT: Brittle cornea syndrome (BCS) is an autosomal recessive disorder characterised by extreme corneal thinning and fragility. Corneal rupture can therefore occur either spontaneously or following minimal trauma in affected patients. Two genes, ZNF469 and PRDM5, have now been identified, in which causative pathogenic mutations collectively account for the condition in nearly all patients with BCS ascertained to date. Therefore, effective molecular diagnosis is now available for affected patients, and those at risk of being heterozygous carriers for BCS. We have previously identified mutations in ZNF469 in 14 families (in addition to 6 reported by others in the literature), and in PRDM5 in 8 families (with 1 further family now published by others). Clinical features include extreme corneal thinning with rupture, high myopia, blue sclerae, deafness of mixed aetiology with hypercompliant tympanic membranes, and variable skeletal manifestations. Corneal rupture may be the presenting feature of BCS, and it is possible that this may be incorrectly attributed to non-accidental injury. Mainstays of management include the prevention of ocular rupture by provision of protective polycarbonate spectacles, careful monitoring of visual and auditory function, and assessment for skeletal complications such as developmental dysplasia of the hip. Effective management depends upon appropriate identification of affected individuals, which may be challenging given the phenotypic overlap of BCS with other connective tissue disorders.
    Orphanet Journal of Rare Diseases 05/2013; 8(1):68. DOI:10.1186/1750-1172-8-68 · 3.36 Impact Factor
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    • "The type associated with loss of ZIP13 function is referred to as spondylocheiro dysplastic-EDS (SCD-EDS), and involves skeletal dysplasia especially in the spine and hands in addition to the classical EDS symptoms (Fukada et al., 2008; Giunta et al., 2008). Collagens of SCD-EDS patients were underhydroxylated although activity of the lysyl and prolyl hydroxylases was normal (Giunta et al., 2008). Slc39a13 knockout mice also showed phenotypic abnormalities that resembled EDS-symptoms, and it was found that ZIP13 was involved in BMP/ TGF-b signaling pathways in connective tissues and nuclear translocation of Smad proteins (Fukada et al., 2008). "
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    ABSTRACT: Zinc is a trace element nutrient that is essential for life. This mineral serves as a cofactor for enzymes that are involved in critical biochemical processes and it plays many structural roles as well. At the cellular level, zinc is tightly regulated and disruption of zinc homeo-stasis results in serious physiological or pathological issues. Despite the high demand for zinc in cells, free or labile zinc must be kept at very low levels. In humans, two major zinc transporter families, the SLC30 (ZnT) family and SLC39 (ZIP) family control cellular zinc homeostasis. This review will focus on the SLC39 transporters. SLC39 transporters primar-ily serve to pass zinc into the cytoplasm, and play critical roles in maintaining cellular zinc homeostasis. These proteins are also significant at the organismal level, and studies are revealing their link to human diseases. Therefore, we will discuss the function, structure, physiology, and pathology of SLC39 transporters.
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