A review of Ehlers-Danlos syndrome

Abstract

Ehlers-Danlos syndrome (EDS) describes a group of heritable disorders of connective tissue comprising mutations in the genes involved in the structure and/or biosynthesis of collagen. Thirteen EDS subtypes are recognized, with a wide degree of symptom overlap among subtypes and with other connective tissue disorders. The clinical hallmarks of EDS are tissue fragility, joint hypermobility, and skin hyperextensibility. Appropriate diagnosis of EDS is important for correct multidisciplinary management and is associated with better clinical outcomes for patients.

The Probable, Possible, and Novel Functions of ERp29

“…Osteogenesis imperfecta (OI), Ehlers-Danos syndrome (EDS) Byers and Steiner, 1992;Myllyharju and Kivirikko, 2001;DiChiara et al, 2016;Miller and Grosel, 2020 Connexin-43 (Cx43) Gap junction alpha-1 protein Oculodentodigital dysplasia (ODDD) Paznekas et al, 2003;Bao et al, 2004;Salameh, 2006;Laird, 2008;Das et al, 2009 PKR-like endoplasmic reticulum kinase (PERK, EIFA2K3) the D. melanogaster Wind protein has a conserved (C-X-X-C) PDI domain (Ma et al, 2003). The important structural and functional homology of the C-terminal D-domain between Wind and human ERp29 (Ma et al, 2003), allowed for better characterization of ERp29 function in earlier studies.…”

“…Recent data implicate ERp29, ERp44, PDIA3, PDIA4, and EroL1 as components of collagen-I's proteostatic network in the ER (DiChiara et al, 2016). While complex, collagen-I biosynthesis includes the critical steps of the hydroxylation of various proline and lysine residues (Yamauchi and Sricholpech, 2012;Miller and Grosel, 2020). These hydroxylysines serve as attachment sites of oligosaccharides and as sites of covalent crosslinking to provide collagen-I it's fibril strength (Yeowell and Walker, 2000), and mutations in several ER-hydroxylases cause specific OI and EDS disorders (Ha-Vinh et al, 2004;Yamauchi and Sricholpech, 2012).…”

“…These hydroxylysines serve as attachment sites of oligosaccharides and as sites of covalent crosslinking to provide collagen-I it's fibril strength (Yeowell and Walker, 2000), and mutations in several ER-hydroxylases cause specific OI and EDS disorders (Ha-Vinh et al, 2004;Yamauchi and Sricholpech, 2012). These ER-resident hydroxylases require ascorbate for proper function (Tajima and Pinnell, 1982;Franceschi et al, 1994) and non-hydroxylated collagen-I is retained in the ER (Miller and Grosel, 2020). Therefore, the presence of ascorbate promotes proper collagen-I processing in the ER while in ascorbate deficient conditions, the immature protein remains in the ER.…”

“…Mutations in the collagen-I gene, COL1A1 , result in various collagenopathies, most notably osteogenesis imperfecta (OI) and Ehlers-Danlos syndrome (EDS). OI and EDS manifest as weakened bone structure and weakened or lax connective tissue, respectively ( Byers and Steiner, 1992 ; Miller and Grosel, 2020 ). Notably, ERp29 has not been implicated as a factor in diseases of collagen-I or related processes to date.…”

“…Depletion of ERp29 does not affect collagen-I secretion in ER-export conditions in the presence of sufficient ascorbate. In contrast, depletion of ERp29 decreases intracellular collagen-I and increases collagen-I secretion in ER-retention conditions when ascorbate is deficient ( Miller and Grosel, 2020 ). Collagen-I and ERp29 may interact at one of the several –(F,Y)-(F,Y)- or –(F,Y)-X-(F,Y)- motifs that are present in collagen-I’s primary structure ( Barak et al, 2009 ).…”