Abstract
The fruit fly Drosophila melanogaster has become an important model organism to investigate metal homeostasis and human diseases. Previously we identified dZIP13 (CG7816), a member of the ZIP transporter family (SLC39A) and presumably a zinc importer, is in fact physiologically primarily responsible to move iron from the cytosol into the secretory compartments in the fly. This review will discuss the implication of this finding for the etiology of Spondylocheirodysplasia-Ehlers-Danlos Syndrome (SCD–EDS), a human disease defective in ZIP13. We propose an entirely different model in that lack of iron in the secretory compartment may underlie SCD-EDS. Altogether three different working models are discussed, supported by relevant findings made in different studies, with uncertainties, and questions remained to be solved. We speculate that the distinct ZIP13 sequence features, different from those of all other ZIP family members, may confer it special transport properties.
Highlights
Frontiers in GeneticsStudy of Drosophila Offers an Alternative Explanation for the Corresponding Human Disease
SPONDYLOCHEIRODYSPLASIA-EHLERS-DANLOS SYNDROME AND ZIP13Ehlers-Danlos syndrome (EDS) is a group of clinically and genetically heterogeneous disorders with defects in connective tissue characterized by skin hyperelasticity, tissue fragility, poor wound healing, and joint hypermobility (Yeowell and Pinnell, 1993; Beighton et al, 1998; Bowen et al, 2017; Brady et al, 2017)
One model proposes that ZIP13 loss of function results in zinc accumulation in ER/Golgi, which competes with iron for binding to lysyl hydroxylase (LH) and PH4, two critical enzymes using iron as a cofactor in the secretory pathway for collagen hydroxylation (Figure 1; Myllyharju, 2008), leading to disruptive biosynthesis of collagens and SCD–EHLERS-DANLOS SYNDROME AND ZIP13Ehlers-Danlos syndrome (EDS) (Figure 2; Fukada et al, 2008; Giunta et al, 2008)
Summary
Study of Drosophila Offers an Alternative Explanation for the Corresponding Human Disease. The fruit fly Drosophila melanogaster has become an important model organism to investigate metal homeostasis and human diseases. We identified dZIP13 (CG7816), a member of the ZIP transporter family (SLC39A) and presumably a zinc importer, is physiologically primarily responsible to move iron from the cytosol into the secretory compartments in the fly. This review will discuss the implication of this finding for the etiology of Spondylocheirodysplasia-Ehlers-Danlos Syndrome (SCD–EDS), a human disease defective in ZIP13. We propose an entirely different model in that lack of iron in the secretory compartment may underlie SCD-EDS. Three different working models are discussed, supported by relevant findings made in different studies, with uncertainties, and questions remained to be solved. We speculate that the distinct ZIP13 sequence features, different from those of all other ZIP family members, may confer it special transport properties
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